3,652 results on '"Novobiocin"'
Search Results
2. In Vitro Evaluation of Anti-Parasitic Activities of Quinolone-Coumarin Hybrids Derived from Fluoroquinolones and Novobiocin Against Toxoplasma gondii.
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Emami, Saeed, Sadeghi, Mitra, Shahdin, Shayesteh, Daryani, Ahmad, Khalilian, Alireza, Pirestani, Majid, Hosseini, Seyed Abdollah, Montazeri, Mahboobeh, Nejad, Zahra Hosseini, and Sarvi, Shahabeddin
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FLUOROQUINOLONES ,ANTIPARASITIC agents ,TOXOPLASMA gondii ,PREGNANT women ,TOXOPLASMOSIS ,IMMUNODEFICIENCY ,CELL survival - Abstract
Purpose: Toxoplasmosis is caused by the parasite Toxoplasma gondii (T. gondii). In immunocompetent individuals, the infection is often asymptomatic; however, in expectant mothers and those with immune system deficiencies, complications may arise. Consequently, there is a need for new drugs that cause minimal damage to host cells. The purpose of this study was to investigate the in vitro antiparasitic efficacy of quinolone–coumarin hybrids QC1–QC12, derived from quinolone antibacterials and novobiocin, against T. gondii. Methods: The derivatives were compared with novobiocin and ciprofloxacin during testing, with pyrimethamine used as a positive control. We conducted the MTT assay to examine the anti-toxoplasmic effects of the test compounds and novobiocin. Evaluation included the infection and proliferation indices, as well as the size and number of plaques, based on the viability of both healthy and infected cells. Results: The in vitro assays revealed that QC1, QC3, QC6, and novobiocin, with selectivity indices (SIs) of 7.27, 13.43, and 8.23, respectively, had the least toxic effect on healthy cells and the highest effect on infected cells compared to pyrimethamine (SI = 3.05). Compared to pyrimethamine, QC1, QC3, QC6, and novobiocin Without having a significant effect on cell viability, demonstrated a significant effect on reducing in both infection index and proliferation index, in addition to reducing the quantity and dimensions of plaques (P < 0.05). Conclusion: Based on our results, QC1, QC3, QC6, and novobiocin due to their significant therapeutic effects could be considered as potential new leads in the development of novel anti-Toxoplasma agents. [ABSTRACT FROM AUTHOR]
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- 2024
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- View/download PDF
3. Revealing the Interaction Mechanism between Mycobacterium tuberculosis GyrB and Novobiocin, SPR719 through Binding Thermodynamics and Dissociation Kinetics Analysis.
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Qiu, Xiaofei, Zhang, Qianqian, Li, Zhaoguo, Zhang, Juan, and Liu, Huanxiang
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MYCOBACTERIUM tuberculosis , *HYDROGEN bonding interactions , *MOLECULAR dynamics , *THERMODYNAMICS , *DNA topoisomerase II - Abstract
With the rapid emergence of drug-resistant strains of Mycobacterium tuberculosis (Mtb), various levels of resistance against existing anti-tuberculosis (TB) drugs have developed. Consequently, the identification of new anti-TB targets and drugs is critically urgent. DNA gyrase subunit B (GyrB) has been identified as a potential anti-TB target, with novobiocin and SPR719 proposed as inhibitors targeting GyrB. Therefore, elucidating the molecular interactions between GyrB and its inhibitors is crucial for the discovery and design of efficient GyrB inhibitors for combating multidrug-resistant TB. In this study, we revealed the detailed binding mechanisms and dissociation processes of the representative inhibitors, novobiocin and SPR719, with GyrB using classical molecular dynamics (MD) simulations, tau-random acceleration molecular dynamics (τ-RAMD) simulations, and steered molecular dynamics (SMD) simulations. Our simulation results demonstrate that both electrostatic and van der Waals interactions contribute favorably to the inhibitors' binding to GyrB, with Asn52, Asp79, Arg82, Lys108, Tyr114, and Arg141 being key residues for the inhibitors' attachment to GyrB. The τ-RAMD simulations indicate that the inhibitors primarily dissociate from the ATP channel. The SMD simulation results reveal that both inhibitors follow a similar dissociation mechanism, requiring the overcoming of hydrophobic interactions and hydrogen bonding interactions formed with the ATP active site. The binding and dissociation mechanisms of GyrB with inhibitors novobiocin and SPR719 obtained in our work will provide new insights for the development of promising GyrB inhibitors. [ABSTRACT FROM AUTHOR]
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- 2024
- Full Text
- View/download PDF
4. A Progressively Disassembled DNA Repair Inhibitors Nanosystem for the Treatment of BRCA Wild-Type Triple-Negative Breast Cancer
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Fang W, Wang J, Ma X, Shao N, Ye K, Zhang D, Shi C, and Luo L
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olaparib ,novobiocin ,tumor microenvironment ,disulfide bonds ,drug release ,magnetic resonance ,Medicine (General) ,R5-920 - Abstract
Weimin Fang,1,2,* Jinghao Wang,3,* Xiaocong Ma,1,2 Ni Shao,1,2 Kunlin Ye,1,2 Dong Zhang,1,2 Changzheng Shi,1,2 Liangping Luo1,2 1Medical Imaging Center, the First Affiliated Hospital of Jinan University, Guangzhou, Guangdong, People’s Republic of China; 2The Guangzhou Key Laboratory of Molecular and Functional Imaging for Clinical Translation, Jinan University, Guangzhou, Guangdong, People’s Republic of China; 3Department of Pharmacy, the First Affiliated Hospital of Jinan University, Guangzhou, Guangdong, People’s Republic of China*These authors contributed equally to this workCorrespondence: Changzheng Shi, Medical Imaging Center, The Guangzhou Key Laboratory of Molecular and Functional Imaging for Clinical Translation, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong, People’s Republic of China, Email tsczcn@jnu.edu.cn Liangping Luo, Medical Imaging Center, The Guangzhou Key Laboratory of Molecular and Functional Imaging for Clinical Translation, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong, People’s Republic of China. Department of Radiology, The Fifth Affiliated Hospital of Jinan University, Guangzhou, Guangdong, People’s Republic of China, Email tluolp@jnu.edu.cnBackground: Olaparib, a poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitor has demonstrated promising efficacy in patients with triple-negative breast cancer (TNBC) carrying breast cancer gene (BRCA) mutations. However, its impact on BRCA wild-type (BRCAwt) TNBC is limited. Hence, it is crucial to sensitize BRCAwt TNBC cells to olaparib for effective clinical practice. Novobiocin, a DNA polymerase theta (POLθ) inhibitor, exhibits sensitivity towards BRCA-mutated cancer cells that have acquired resistance to PARP inhibitors. Although both of these DNA repair inhibitors demonstrate therapeutic efficacy in BRCA-mutated cancers, their nanomedicine formulations’ antitumor effects on wild-type cancer remain unclear. Furthermore, ensuring effective drug accumulation and release at the cancer site is essential for the clinical application of olaparib.Materials and Methods: Herein, we designed a progressively disassembled nanosystem of DNA repair inhibitors as a novel strategy to enhance the effectiveness of olaparib in BRCAwt TNBC. The nanosystem enabled synergistic delivery of two DNA repair inhibitors olaparib and novobiocin, within an ultrathin silica framework interconnected by disulfide bonds.Results: The designed nanosystem demonstrated remarkable capabilities, including long-term molecular storage and specific drug release triggered by the tumor microenvironment. Furthermore, the nanosystem exhibited potent inhibitory effects on cell viability, enhanced accumulation of DNA damage, and promotion of apoptosis in BRCAwt TNBC cells. Additionally, the nanosystem effectively accumulated within BRCAwt TNBC, leading to significant growth inhibition and displaying vascular regulatory abilities as assessed by magnetic resonance imaging (MRI).Conclusion: Our results provided the inaugural evidence showcasing the potential of a progressively disassembled nanosystem of DNA repair inhibitors, as a promising strategy for the treatment of BRCA wild-type triple-negative breast cancer.Keywords: olaparib, novobiocin, tumor microenvironment, disulfide bonds, drug release, magnetic resonance
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- 2023
5. Plausible inhibitors of malaria parasite Plasmodium falciparum 3D7 ATP-dependent DNA helicase.
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Alkurbi, Mohammad Othman
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PLASMODIUM falciparum , *DNA helicases , *PROTOZOA , *MALARIA vaccines , *MOLECULAR docking , *MOLECULAR orbitals - Abstract
Background: Plasmodium falciparum is a parasite (protozoa) of humans, & the lethal species of Plasmodium that affects malaria in humans. In the lack of a medically validated malaria vaccine, nearby are merely a few inexpensive medications available for therapy. Studies of diverse enzymes used in pharmaceutical drug discovery become essential aspects. The theoretical analysis helps to screen novel drug candidates. Methods: Here we have optimized three biologically active compounds, netropsin, nogalamycin, and novobiocin, and also carried out a molecular docking study with the protein ATP-dependent DNA helicase (UvrD) Plasmodium falciparum 3D7. Results: The plasmoDB id of the designated protein is PF3D7-0514100. Our calculations show that netropsin, nogalamycin, and novobiocin can have an affinity with the Plasmodium falciparum. Conclusion: Our study also predicted that novobiocin would give a better result with this protein than netropsin and nogalamycin. The frontier molecular orbitals & electrostatic potential (MEP) maps also support the higher activity of the novobiocin compound. [ABSTRACT FROM AUTHOR]
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- 2023
6. A comparative approach to confirm antibiotic-resistant microbes in the cryosphere.
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Gattinger, Daniel, Pichler, Katrin, Weil, Tobias, and Sattler, Birgit
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COMPARATIVE method ,CRYOSPHERE ,MICROBIAL sensitivity tests ,DRUG resistance in bacteria ,DRUG resistance in microorganisms - Abstract
Antibiotic-resistant microbes pose one of the biggest challenges of the current century. While areas with proximity to human impact are closely studied, a lot is yet to learn about antimicrobial resistance in remote regions like the cryosphere. Nowadays, antibiotic (AB) resistance is considered a pollution that has reached the Earth's most pristine areas. However, monitoring of resistant environmental bacteria therein faces several challenges that inhibit scientific progress in this field. Due to many cultivation-based antibiotic susceptibility tests being optimized for mesophilic pathogenic microorganisms, many researchers opt for expensive molecular biological approaches to detect antibiotic resistance in the cryosphere. However, some disadvantages of these methods prohibit effective comprehensive monitoring of resistant bacteria in pristine areas, hence we suggest established cultivation-based approaches when looking for antimicrobial resistance in the cryosphere. In this study, we compared two common antibiotic susceptibility tests and optimized them to meet the needs of psychrophilic microorganisms. The resulting cultures thereof originated from cryospheric habitats with differing anthropogenic impacts. The results show that these methods are applicable to detect antibiotic resistance in cryospheric habitats and could potentially increase the comparability between studies. [ABSTRACT FROM AUTHOR]
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- 2023
- Full Text
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7. A first-in-class Polymerase Theta Inhibitor selectively targets Homologous-Recombination-Deficient Tumors.
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Zhou, Jia, Gelot, Camille, Pantelidou, Constantia, Li, Adam, Yücel, Hatice, Davis, Rachel, Färkkilä, Anniina, Kochupurakkal, Bose, Syed, Aleem, Shapiro, Geoffrey, Tainer, John, Blagg, Brian, Ceccaldi, Raphael, and DAndrea, Alan
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Fanconi Anemia ,HRD cancer ,Homologous Recombination ,MMEJ ,Novobiocin ,PARP inhibitor resistance ,Polymerase theta (POLθ) ,Adenosine Triphosphatases ,Female ,Homologous Recombination ,Humans ,Ovarian Neoplasms ,Poly(ADP-ribose) Polymerase Inhibitors - Abstract
DNA polymerase theta (POLθ) is synthetic lethal with Homologous Recombination (HR) deficiency and thus a candidate target for HR-deficient cancers. Through high-throughput small molecule screens we identified the antibiotic Novobiocin (NVB) as a specific POLθ inhibitor that selectively kills HR-deficient tumor cells in vitro and in vivo. NVB directly binds to the POLθ ATPase domain, inhibits its ATPase activity, and phenocopies POLθ depletion. NVB kills HR-deficient breast and ovarian tumors in GEMM, xenograft and PDX models. Increased POLθ levels predict NVB sensitivity, and BRCA-deficient tumor cells with acquired resistance to PARP inhibitors (PARPi) are sensitive to NVB in vitro and in vivo. Mechanistically, NVB-mediated cell death in PARPi-resistant cells arises from increased double-strand break end resection, leading to accumulation of single-strand DNA intermediates and non-functional RAD51 foci. Our results demonstrate that NVB may be useful alone or in combination with PARPi in treating HR-deficient tumors, including those with acquired PARPi resistance. (151/150).
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- 2021
8. Revealing the Interaction Mechanism between Mycobacterium tuberculosis GyrB and Novobiocin, SPR719 through Binding Thermodynamics and Dissociation Kinetics Analysis
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Xiaofei Qiu, Qianqian Zhang, Zhaoguo Li, Juan Zhang, and Huanxiang Liu
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tuberculosis ,GyrB ,novobiocin ,SPR719 ,molecular dynamics (MD) simulations ,binding mechanism ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
With the rapid emergence of drug-resistant strains of Mycobacterium tuberculosis (Mtb), various levels of resistance against existing anti-tuberculosis (TB) drugs have developed. Consequently, the identification of new anti-TB targets and drugs is critically urgent. DNA gyrase subunit B (GyrB) has been identified as a potential anti-TB target, with novobiocin and SPR719 proposed as inhibitors targeting GyrB. Therefore, elucidating the molecular interactions between GyrB and its inhibitors is crucial for the discovery and design of efficient GyrB inhibitors for combating multidrug-resistant TB. In this study, we revealed the detailed binding mechanisms and dissociation processes of the representative inhibitors, novobiocin and SPR719, with GyrB using classical molecular dynamics (MD) simulations, tau-random acceleration molecular dynamics (τ-RAMD) simulations, and steered molecular dynamics (SMD) simulations. Our simulation results demonstrate that both electrostatic and van der Waals interactions contribute favorably to the inhibitors’ binding to GyrB, with Asn52, Asp79, Arg82, Lys108, Tyr114, and Arg141 being key residues for the inhibitors’ attachment to GyrB. The τ-RAMD simulations indicate that the inhibitors primarily dissociate from the ATP channel. The SMD simulation results reveal that both inhibitors follow a similar dissociation mechanism, requiring the overcoming of hydrophobic interactions and hydrogen bonding interactions formed with the ATP active site. The binding and dissociation mechanisms of GyrB with inhibitors novobiocin and SPR719 obtained in our work will provide new insights for the development of promising GyrB inhibitors.
- Published
- 2024
- Full Text
- View/download PDF
9. A comparative approach to confirm antibiotic-resistant microbes in the cryosphere
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Daniel Gattinger, Katrin Pichler, Tobias Weil, and Birgit Sattler
- Subjects
antibiotic resistance ,EUCAST diffusion test ,vancomycin ,novobiocin ,cold habitats ,anthropogenic influence ,Microbiology ,QR1-502 - Abstract
Antibiotic-resistant microbes pose one of the biggest challenges of the current century. While areas with proximity to human impact are closely studied, a lot is yet to learn about antimicrobial resistance in remote regions like the cryosphere. Nowadays, antibiotic (AB) resistance is considered a pollution that has reached the Earth’s most pristine areas. However, monitoring of resistant environmental bacteria therein faces several challenges that inhibit scientific progress in this field. Due to many cultivation-based antibiotic susceptibility tests being optimized for mesophilic pathogenic microorganisms, many researchers opt for expensive molecular biological approaches to detect antibiotic resistance in the cryosphere. However, some disadvantages of these methods prohibit effective comprehensive monitoring of resistant bacteria in pristine areas, hence we suggest established cultivation-based approaches when looking for antimicrobial resistance in the cryosphere. In this study, we compared two common antibiotic susceptibility tests and optimized them to meet the needs of psychrophilic microorganisms. The resulting cultures thereof originated from cryospheric habitats with differing anthropogenic impacts. The results show that these methods are applicable to detect antibiotic resistance in cryospheric habitats and could potentially increase the comparability between studies.
- Published
- 2023
- Full Text
- View/download PDF
10. Fluorescence Emission and Molecular Docking Studies Identified Novobiocin as a Potent Inhibitor of the Japanese Encephalitis Virus (JEV) Envelope Protein.
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Alwabli, Afaf S.
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JAPANESE encephalitis viruses , *JAPANESE B encephalitis , *CENTRAL nervous system diseases , *FLUORESCENCE spectroscopy , *VIRUS diseases - Abstract
Introduction: The Japanese Encephalitis Virus (JEV) causes the acute inflammatory disease of the central nervous system known as Japanese encephalitis. JEV is a RNA virus (+strand) that is tiny, enclosed, and from the family Flavivirus. The envelope protein (E), which facilitates JEV entrance into the host cell, has been chosen as a possible molecular aim for therapeutic progress in this work. Materials and Methods: The 3D structure of E protein was retrieved from RCSB PDB (id: 3P54). The sdf files of four lead molecules namely etoposide, netropsin, nogalamycin, and novobiocin were downloaded from the PubChem and used for molecular docking against JEV E protein. We then assessed the fluorescence emission intensity of JEV alone and JEV bound to novobiocin at 280–500 nM to confirm the inhibition of JEV by Novobiocin. The secondary structure of JEV was ascertained by measuring its CD spectra. The CD spectra of JEV were examined as a function of temperature to evaluate the protein constancy. Results: Our docking and fluorescence emission spectra results showed that JEV E pro has good binding preference for novobiocin among these four test compounds. Moreover, fluorescence emission spectra of JEV E protein with novobiocin also revealed the 5 µM concentration is an effective novobiocin concentration to inhibit the activity of target protein. One top ranked lead molecule namely novobiocin with strong binding affinity (-8.574 Kcal/mol) to JEV E protein was known based on binding energy. Results of the CD Spectra made it quite evident that there is no random coil. Peaks in the negative range (troughs) at 210–230 nm in the CD spectra indicate that JEV has a secondary structure rich in helices. The data unambiguously show that there is no appreciable variation in the JEV curves. Conclusion: Conclusion of the current work offer a thorough understanding of how the JEV E protein is inhibited and provide information that will help novobiocin be developed as a therapeutic drug against JEV E protein in certain viral diseases. [ABSTRACT FROM AUTHOR]
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- 2023
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11. Binding of Novobiocin Paves the Way for Inhibition of DEAH-box Helicase 8.
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Ajmal, Mohammad Rehan, Almutairi, Fahad Mohammad, Hussain, Arif, Ullah, Mohammad Fahad, Ahmad, M. Ayaz, Abdelhameed, Ali Saber, and Arif, Hussain
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FLUORESCENCE spectroscopy ,MOLECULAR spectra ,RNA helicase ,MOLECULAR docking ,SOCIAL interaction - Abstract
Introduction: DEAH-box helicase 8 (DHX8) is a crucial DEAH-box RNA helicase involved in splicing and required for the release of mature mRNA from the splice. Here, we report the interaction study of human DHX8 and four test compounds namely etoposide, netropsin, nogalamycin, and novobiocin. Materials and Methods: Molecular docking and fluorescence emission spectra techniques were employed to determine the binding and inhibitory effect of test compounds. Results: Our docking and fluorescence emission spectra results showed that DHX8 has a good binding preference for novobiocin among these four test compounds. Moreover, fluorescence emission spectra of DHX8 with novobiocin also revealed the 2.5 µM concentration is an effective novobiocin concentration to inhibit the activity of DHX8. Conclusion: These findings provide an in-depth understanding of the inhibition of DHX8 and contribute insights towards the development of novobiocin as a therapeutic molecule against the DHX8 in targeted diseases. [ABSTRACT FROM AUTHOR]
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- 2023
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12. Patients Response to Early Switch To Oral:Osteomyelitis Study (PRESTO:Osteo)
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University of Louisville and Julio Ramirez, Professor of Medicine
- Published
- 2021
13. The synthesis, biological evaluation, and fluorescence study of 3-aminocoumarin and their derivatives: a brief review.
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Patra, Prasanta, Manna, Sibasis, Patra, Susanta, and Samanta, Khokan
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3-Aminocoumarins and their derivatives represent an important class of a multi-tasking and multi-functional scaffold in organic synthesis. So, the synthesis of 3-aminocoumarins and their synthetic applicability have an immense impact in the field of organic and pharmaceutical chemistry due to various biological activities displayed by such class of compounds as well as due to their natural occurrences. The chemical reactivity of 3-aminocoumarins is more profound due to the presence of an amino group as well as enamine carbon in the described scaffold. The objective of this present review was to focus on different synthetic methodologies, for the synthesis of 3-aminocoumarin derivatives and their biological evaluation and fluorescence study. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
14. Docking simulation and antibiotic discovery targeting the MlaC protein in Gram‐negative bacteria
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Huang, Yu‐ming M, Munguia, Jason, Miao, Yinglong, Nizet, Victor, and McCammon, J Andrew
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Biochemistry and Cell Biology ,Medicinal and Biomolecular Chemistry ,Chemical Sciences ,Biological Sciences ,Infectious Diseases ,5.1 Pharmaceuticals ,Development of treatments and therapeutic interventions ,Generic health relevance ,Anti-Bacterial Agents ,Bacterial Proteins ,Binding Sites ,Gram-Negative Bacteria ,Membrane Transport Proteins ,Molecular Docking Simulation ,Novobiocin ,Phospholipids ,Protein Structure ,Tertiary ,antibiotic ,drug design ,MlaC protein ,virtual screening ,Biophysics ,Medicinal & Biomolecular Chemistry ,Biochemistry and cell biology ,Medicinal and biomolecular chemistry - Abstract
To maintain the lipid asymmetry of the cell envelope in Gram-negative bacteria, the MlaC protein serves as a lipid transfer factor and delivers phospholipids from the outer to the inner membrane. A strategy of antibiotic discovery is to design a proper compound that can tightly bind to the MlaC protein and inhibit the MlaC function. In this study, we performed virtual screening on multiple MlaC structures obtained from molecular dynamics simulations to identify potential MlaC binders. Our results suggested that clorobiocin is a compound that could bind to the MlaC protein. Through the comparison of the bound geometry between clorobiocin and novobiocin, we pointed out that the methyl-pyrrole group of the noviose sugar in clorobiocin forms hydrophobic interactions with amino acids in the phospholipid binding pocket, which allows the compound to bind deep in the active site. This also explains why clorobiocin shows a tighter binding affinity than novobiocin. Our study highlights a practical path of antibiotic development against Gram-negative bacteria.
- Published
- 2019
15. Efficacy of Treatment with the Antibiotic Novobiocin against Infection with Bacillus anthracis or Burkholderia pseudomallei.
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Klimko, Christopher P., Welkos, Susan L., Shoe, Jennifer L., Mou, Sherry, Hunter, Melissa, Rill, Nathaniel O., DeShazer, David, and Cote, Christopher K.
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BURKHOLDERIA pseudomallei ,MELIOIDOSIS ,BACILLUS anthracis ,ANTIBIOTICS ,ANIMAL diseases ,SPOREFORMING bacteria - Abstract
The microbial pathogens Burkholderia pseudomallei and Bacillus anthracis are unrelated bacteria, yet both are the etiologic agents of naturally occurring diseases in animals and humans and are classified as Tier 1 potential biothreat agents. B. pseudomallei is the gram-negative bacterial agent of melioidosis, a major cause of sepsis and mortality globally in endemic tropical and subtropical regions. B. anthracis is the gram-positive spore-forming bacterium that causes anthrax. Infections acquired by inhalation of these pathogens are challenging to detect early while the prognosis is best; and they possess innate multiple antibiotic resistance or are amenable to engineered resistance. Previous studies showed that the early generation, rarely used aminocoumarin novobiocin was very effective in vitro against a range of highly disparate biothreat agents. The objective of the current research was to begin to characterize the therapeutic efficacy of novobiocin in mouse models of anthrax and melioidosis. The antibiotic was highly efficacious against infections by both pathogens, especially B. pseudomallei. Our results supported the concept that specific older generation antimicrobials can be effective countermeasures against infection by bacterial biothreat agents. Finally, novobiocin was shown to be a potential candidate for inclusion in a combined pre-exposure vaccination and post-exposure treatment strategy designed to target bacterial pathogens refractory to a single medical countermeasure. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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16. DNA Gyrase Inhibitors Increase the Frequency of Bacteriophage-like RcGTA-Mediated Gene Transfer in Rhodobacter capsulatus.
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Bernelot-Moens, Rachel and Beatty, J. Thomas
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DNA topoisomerase II , *GENETIC transformation , *HORIZONTAL gene transfer , *ANTIBIOTICS , *GENE frequency - Abstract
Rhodobacter capsulatus produces a bacteriophage-like particle called the gene transfer agent (RcGTA) that mediates horizontal gene transfer. RcGTA particles transfer random ~4.5-kb fragments of genomic DNA that integrate into recipient genomes by allelic replacement. This work addresses the effect of sub-inhibitory concentrations of antibiotics on gene transfer by RcGTA. A transduction assay was developed to test the effects of various substances on gene transfer. Using this assay, low concentrations of DNA gyrase inhibitors were found to increase the frequency of gene transfer. Novobiocin was studied in more detail, and it was found that this antibiotic did not influence the production or release of RcGTA but instead appeared to act on the recipient cells. The target of novobiocin in other species has been shown to be the GyrB subunit of DNA gyrase (a heterotetramer of 2GyrA and 2GyrB). R. capsulatus encodes GyrA and GyrB homologues, and a GyrB overexpression plasmid was created and found to confer resistance to novobiocin. The presence of the overexpression plasmid in recipient cells greatly diminished the novobiocin-mediated increase in gene transfer, confirming that this effect is due to the binding of novobiocin by GyrB. The results of this work show that antibiotics affect gene transfer in R. capsulatus and may be relevant to microbial genetic exchange in natural ecosystems. [ABSTRACT FROM AUTHOR]
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- 2022
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17. Antimicrobial release from a lipid bilayer titanium implant coating is triggered by Staphylococcus aureus alpha-haemolysin.
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Azizova, Liana, Al Dalaty, Adnan, Brousseau, Emmanuel, Birchall, James, Wilkinson, Thomas, Sloan, Alastair, and Nishio Ayre, Wayne
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QUARTZ crystal microbalances , *MESENCHYMAL stem cells , *ARTHROPLASTY , *ATOMIC force microscopy , *CONTACT angle - Abstract
[Display omitted] • The formation of a supported lipid bilayer (SLB) containing an aminocoumarin antibiotic (novobiocin) on the surface of titanium (Ti) discs modified with octadecylphosphonic acid (ODPA) was confirmed by quartz crystal microbalance, water contact angle and atomic force microscopy data. • The SLB with encapsulated novobiocin showed reduced attachment and viability of Staphylococcus aureus when compared to untreated Ti. • Release of a fluorescent probe (6-FAM) from the SLB-modified Ti was triggered by different concentrations of α-haemolysin (0.1–10 μg/mL) in a dose-dependent manner. Infections represent a significant challenge in joint replacements, often leading to the need for high-risk revision surgeries. There is an unmet need for novel technologies that are triggered by pathogens to prevent long-term joint replacement infections. The use of supported lipid bilayers (SLBs) with encapsulated antimicrobial agents, which are responsive to bacterial virulence factors, offers an exciting approach to achieving this goal. In this study, Ti was functionalised using octadecylphosphonic acid (ODPA) to form an SLB with an encapsulated antibiotic (novobiocin), effective against methicillin-resistant Staphylococcus aureus. Using the solvent-assisted method, the SLB with encapsulated novobiocin was developed on the surface of ODPA-modified Ti quartz crystal microbalance (QCM) sensors. QCM monitoring and fluorescence microscopy supported the successful formation of a planar SLB with encapsulated novobiocin. Incorporation of novobiocin in the SLB resulted in significantly reduced attachment and viability of S. aureus NCTC 7791, with no significant reduction in human bone marrow stromal cell viability. Additionally, in the presence of varying concentrations of α-haemolysin, a virulence factor from S. aureus , the SLB demonstrated a dose-dependent release pattern. The findings indicate the possibility of creating a biocompatible implant coating that releases an antimicrobial in the presence of a bacterial virulence factor, in a dose-dependent manner. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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18. New Life of an Old Drug: Caffeine as a Modulator of Antibacterial Activity of Commonly Used Antibiotics.
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Woziwodzka, Anna, Krychowiak-Maśnicka, Marta, Gołuński, Grzegorz, Łosiewska, Anna, Borowik, Agnieszka, Wyrzykowski, Dariusz, and Piosik, Jacek
- Subjects
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CAFFEINE , *ANTIBACTERIAL agents , *ANTIBIOTICS , *METHICILLIN-resistant staphylococcus aureus , *CEFEPIME , *GRAM-negative bacteria , *ACINETOBACTER baumannii - Abstract
With the rapid and continuous emergence of antimicrobial resistance, bacterial infections became a significant global healthcare concern. One of the proposed strategies to combat multidrug-resistant pathogens is to use additional compounds, such as natural biologically active substances, as adjuvants for existing antibiotics. In this study, we investigated the potential of caffeine, the widely consumed alkaloid, to modulate the antibacterial effects of antibiotics commonly used in clinical practice. We used disc diffusion assay to evaluate the effects of caffeine on 40 antibiotics in two Staphylococcus aureus strains (methicillin-resistant and methicillin-sensitive). Based on the results of this step, we selected five antibiotics for which the greatest caffeine-induced improvements in antibacterial activity were observed, and further analyzed their interactions with caffeine using a checkerboard approach. Caffeine at concentrations of 250 µg/mL or higher halved the MIC values of ticarcillin, cefepime, gentamycin, azithromycin, and novobiocin for all gram-negative species investigated (Pseudomonas aeruginosa, Klebsiella pneumoniae, and Acinetobacter baumannii). At the highest caffeine concentrations tested (up to 16 mg/mL), decreases in MIC values were 8- to 16-fold. The obtained results prove that caffeine modulates the activity of structurally diverse antibiotics, with the most promising synergistic effects observed for cefepime and azithromycin toward gram-negative pathogens. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
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19. Recent developments of topoisomerase inhibitors: Clinical trials, emerging indications, novel molecules and global sales.
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Bondarev AD, Jonsson J, Chubarev VN, Tarasov VV, Lagunas-Rangel FA, and Schiöth HB
- Abstract
The nucleic acid topoisomerases (TOP) are an evolutionary conserved mechanism to solve topological problems within DNA and RNA that have been historically well-established as a chemotherapeutic target. During investigation of trends within clinical trials, we have identified a very high number of clinical trials involving TOP inhibitors, prompting us to further evaluate the current status of this class of therapeutic agents. In total, we have identified 233 unique molecules with TOP-inhibiting activity. In this review, we provide an overview of the clinical drug development highlighting advances in current clinical uses and discussing novel drugs and indications under development. A wide range of bacterial infections, along with solid and hematologic neoplasms, represent the bulk of clinically approved indications. Negative ADR profile and drug resistance among the antibacterial TOP inhibitors and anthracycline-mediated cardiotoxicity in the antineoplastic TOP inhibitors are major points of concern, subject to continuous research efforts. Ongoing development continues to focus on bacterial infections and cancer; however, there is a degree of diversification in terms of novel drug classes and previously uncovered indications, such as glioblastoma multiforme or Clostridium difficile infections. Preclinical studies show potential in viral, protozoal, parasitic and fungal infections as well and suggest the emergence of a novel target, TOP IIIβ. We predict further growth and diversification of the field thanks to the large number of experimental TOP inhibitors emerging., Competing Interests: Declaration of Competing Interest The authors whose names are listed immediately below certify that they have NO affiliations with or involvement in any organization or entity with any financial interest (such as honoraria; educational grants; participation in speakers’ bureaus; membership, employment, consultancies, stock ownership, or other equity interest; and expert testimony or patent-licensing arrangements), or non-financial interest (such as personal or professional relationships, affiliations, knowledge or beliefs) in the subject matter or materials discussed in this manuscript., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)
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- 2024
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20. Talazoparib enhances resection at DSBs and renders HR-proficient cancer cells susceptible to Polθ inhibition.
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Lin X, Soni A, Hessenow R, Sun Y, Mladenov E, Guberina M, Stuschke M, and Iliakis G
- Abstract
Background and Purpose: The PARP inhibitor (PARPi), Talazoparib (BMN673), effectively and specifically radiosensitizes cancer cells. Radiosensitization is mediated by a shift in the repair of ionizing radiation (IR)-induced DNA double-strand breaks (DSBs) toward PARP1-independent, alternative end-joining (alt-EJ). DNA polymerase theta (Polθ) is a key component of this PARP1-independent alt-EJ pathway and we show here that its inhibition can further radiosensitize talazoparib-treated cells. The purpose of the present work is to explore mechanisms and dynamics underpinning enhanced talazoparib radiosensitization by Polθ inhibitors in HR-proficient cancer cells., Methods and Materials: Radiosensitization to PARPis, talazoparib, olaparib, rucaparib and veliparib was assessed by clonogenic survival. Polθ-proficient and -deficient cells were treated with PARPis and/or with the Polθ inhibitors ART558 or novobiocin. The role of DNA end-resection was studied by down-regulating CtIP and MRE11 expression using siRNAs. DSB repair was assessed by scoring γH2AX foci. The formation of chromosomal abnormalities was assessed as evidence of alt-EJ function using G
2 -specific cytogenetic analysis., Results: Talazoparib exerted pronounced radiosensitization that varied among the tested cancer cell lines; however, radiosensitization was undetectable in normal cells. Other commonly used PARPis, olaparib, veliparib, or rucaparib were ineffective radiosensitizers under our experimental conditions. Although genetic ablation or pharmacological inhibition of Polθ only mildly radiosensitized cancer cells, talazoparib-treated cells were markedly further radiosensitized. Mechanistically, talazoparib shunted DSBs to Polθ-dependent alt-EJ by enhancing DNA end-resection in a CtIP- and MRE11-dependent manner - an effect detectable at low, but not high IR doses. Chromosomal translocation analysis in talazoparib-treated cells exposed to Polθ inhibitors suggested that PARP1- and Polθ-dependent alt-EJ pathways may complement, but also back up each other., Conclusion: We propose that talazoparib promotes low-dose, CtIP/MRE11-dependent resection and increases the reliance of irradiated HR-proficient cancer cells, on Polθ-mediated alt-EJ. The combination of Polθ inhibitors with talazoparib suppresses this option and causes further radiosensitization. The results suggest that Polθ inhibition may be exploited to maximize talazoparib radiosensitization of HR-proficient tumors in the clinic., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)- Published
- 2024
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21. Integrated Genotoxicity Testing of three anti-infective drugs using the TGx-DDI transcriptomic biomarker and high-throughput CometChip® assay in TK6 cells
- Author
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Julie K. Buick, Andrea Rowan-Carroll, Rémi Gagné, Andrew Williams, Renxiang Chen, Heng-Hong Li, Albert J. Fornace, Christy Chao, Bevin P. Engelward, Roland Frötschl, Heidrun Ellinger-Ziegelbauer, Syril D. Pettit, Jiri Aubrecht, and Carole L. Yauk
- Subjects
genetic toxicology ,TGx-28.65 genomic biomarker ,toxicogenomics ,nitrofurantoin ,metronidazole ,novobiocin ,Toxicology. Poisons ,RA1190-1270 - Abstract
Genotoxicity testing relies on the detection of gene mutations and chromosome damage and has been used in the genetic safety assessment of drugs and chemicals for decades. However, the results of standard genotoxicity tests are often difficult to interpret due to lack of mode of action information. The TGx-DDI transcriptomic biomarker provides mechanistic information on the DNA damage-inducing (DDI) capability of chemicals to aid in the interpretation of positive in vitro genotoxicity data. The CometChip® assay was developed to assess DNA strand breaks in a higher-throughput format. We paired the TGx-DDI biomarker with the CometChip® assay in TK6 cells to evaluate three model agents: nitrofurantoin (NIT), metronidazole (MTZ), and novobiocin (NOV). TGx-DDI was analyzed by two independent labs and technologies (nCounter® and TempO-Seq®). Although these anti-infective drugs are, or have been, used in human and/or veterinary medicine, the standard genotoxicity testing battery showed significant genetic safety findings. Specifically, NIT is a mutagen and causes chromosome damage, and MTZ and NOV cause chromosome damage in conventional in vitro tests. Herein, the TGx-DDI biomarker classified NIT and MTZ as non-DDI at all concentrations tested, suggesting that NIT’s mutagenic activity is bacterial specific and that the observed chromosome damage by MTZ might be a consequence of in vitro test conditions. In contrast, NOV was classified as DDI at the second highest concentration tested, which is in line with the fact that NOV is a bacterial DNA-gyrase inhibitor that also affects topoisomerase II at high concentrations. The lack of DNA damage for NIT and MTZ was confirmed by the CometChip® results, which were negative for all three drugs except at overtly cytotoxic concentrations. This case study demonstrates the utility of combining the TGx-DDI biomarker and CometChip® to resolve conflicting genotoxicity data and provides further validation to support the reproducibility of the biomarker.
- Published
- 2022
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22. A monoclonal antibody-based colloidal gold immunochromatographic strip for the analysis of novobiocin in beef and chicken.
- Author
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Jiang, Hongtao, Xu, Xinxin, Song, Shanshan, Wu, Aihong, Liu, Liqiang, Kuang, Hua, and Xu, Chuanlai
- Subjects
- *
COLLOIDAL gold , *MONOCLONAL antibodies , *ENZYME-linked immunosorbent assay , *CHICKEN as food - Abstract
In this study, a monoclonal antibody (mAb) 1G5 against novobiocin with high sensitivity and specificity was prepared from a newly-designed hapten. According to the results of an indirect competitive enzyme-linked immunosorbent assay (ic-ELISA), the 50%-inhibitory concentration of the anti-novobiocin mAb was 6.9 ng/mL and the cross-reactivity was less than 0.1% to its analogues. Furthermore, a rapid colloidal gold immunochromatographic assay (ICA) was successfully developed for the determination of novobiocin in spiked samples. Two calibration curves were established respectively, for beef and chicken samples. The ICA results showed a visual colorimetric value of 50 ng/mL and a cut-off value of 300 ng/mL in beef samples. The ICA results of chicken samples were almost the same as that of beef. When quantitative detection was performed using a strip reader, the detection ranges for quantitative analysis in beef and chicken were 23.7–287.5 and 19.7–263.8 µg/kg respectively. Recoveries were between 82.7 and 95.3% for beef samples with the coefficient of variation (CV) ranging from 2.5 to 5.1%. Recoveries were in the range of 89.6–105.5% with the CV ranging from 2.9% to 6.3% for chicken samples. Importantly, these results from the ICA were highly consistent with the results obtained by LC-MS/MS. Therefore, this ICA could be used as an alternative means for the rapid determination of NOV in a large number of beef and chicken samples. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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23. Antimicrobial activities of amphiphilic cationic polymers and their efficacy of combination with novobiocin.
- Author
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Miyagawa, Atsushi, Ohno, Shinya, Hattori, Tomohiko, and Yamamura, Hatsuo
- Subjects
- *
CATIONIC polymers , *ANTIBIOTICS , *ANTI-infective agents , *ANTIMICROBIAL polymers , *MOLECULAR weights , *STAPHYLOCOCCUS aureus , *ESCHERICHIA coli , *POLYMERS - Abstract
Today, drug-resistant bacteria represent a significant problem worldwide. In fact, bacteria are becoming resistant even to newly developed antibiotics. Therefore, there is an urgent need to develop antibiotics to which bacteria cannot become resistant. In this study, antimicrobial polymers to which bacteria cannot develop resistance were prepared from 6-aminohexyl methacrylamide and N-isopropyl acrylamide. The polymers with molecular weights of the order of 105 showed little antimicrobial activity against Staphylococcus aureus and Escherichia coli as well as low toxicity. On the other hand, polymers with lower molecular weights (of the order of 104) did show antimicrobial activity against S. aureus and E. coli. These polymers were combined with novobiocin to investigate the combined usage effects against E. coli. The combined usage of novobiocin and the low-molecular-weight polymers reduced the minimum inhibitory concentration, which was less than 0.0625 μg/mL against E. coli. This result indicates that the combination is useful for increasing the efficacy of antibiotics and broadening their antimicrobial spectrum. Furthermore, the results showed the possibility that the antimicrobial polymers serve not only as antibiotics to which bacteria have not developed resistance but also as adjuvants for other antibiotics. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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24. Modification of Salmonella Lipopolysaccharides Prevents the Outer Membrane Penetration of Novobiocin
- Author
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Nobre, Thatyane M, Martynowycz, Michael W, Andreev, Konstantin, Kuzmenko, Ivan, Nikaido, Hiroshi, and Gidalevitz, David
- Subjects
Microbiology ,Biological Sciences ,Prevention ,Infectious Diseases ,Emerging Infectious Diseases ,Anti-Bacterial Agents ,Bacterial Proteins ,Cell Membrane ,Hydrophobic and Hydrophilic Interactions ,Lipid A ,Lipopolysaccharides ,Novobiocin ,Permeability ,Salmonella ,Physical Sciences ,Chemical Sciences ,Biophysics ,Biological sciences ,Chemical sciences ,Physical sciences - Abstract
Small hydrophilic antibiotics traverse the outer membrane of Gram-negative bacteria through porin channels. Large lipophilic agents traverse the outer membrane through its bilayer, containing a majority of lipopolysaccharides in its outer leaflet. Genes controlled by the two-component regulatory system PhoPQ modify lipopolysaccharides. We isolate lipopolysaccharides from isogenic mutants of Salmonella sp., one lacking the modification, the other fully modified. These lipopolysaccharides were reconstituted as monolayers at the air-water interface, and their properties, as well as their interaction with a large lipophilic drug, novobiocin, was studied. X-ray reflectivity showed that the drug penetrated the monolayer of the unmodified lipopolysaccharides reaching the hydrophobic region, but was prevented from this penetration into the modified lipopolysaccharides. Results correlate with behavior of bacterial cells, which become resistant to antibiotics after PhoPQ-regulated modifications. Grazing incidence x-ray diffraction showed that novobiocin produced a striking increase in crystalline coherence length, and the size of the near-crystalline domains.
- Published
- 2015
25. Dioctanoyl Ultrashort Tetrabasic β-Peptides Sensitize Multidrug-Resistant Gram-Negative Bacteria to Novobiocin and Rifampicin.
- Author
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Ramirez, Danyel, Berry, Liam, Domalaon, Ronald, Li, Yanqi, Arthur, Gilbert, Kumar, Ayush, and Schweizer, Frank
- Subjects
GRAM-negative bacteria ,RIFAMPIN ,ENTEROBACTER cloacae ,KLEBSIELLA pneumoniae ,ACINETOBACTER baumannii ,ANTIBACTERIAL agents ,PSEUDOMONAS aeruginosa ,ANTIBIOTICS - Abstract
Recently reported peptidomimetics with increased resistance to trypsin were shown to sensitize priority multidrug-resistant (MDR) Gram-negative bacteria to novobiocin and rifampicin. To further optimize proteolytic stability, β-amino acid-containing derivatives of these compounds were prepared, resulting in three dioctanoyl ultrashort tetrabasic β-peptides (dUSTBβPs). The nonhemolytic dUSTBβP 3, comprised of three β
3 -homoarginine residues and two fatty acyl tails eight carbons long, enhanced the antibacterial activity of various antibiotics from different classes. Notably, compound 3 retained the ability to potentiate novobiocin and rifampicin in wild-type Gram-negative bacteria against MDR clinical isolates of Pseudomonas aeruginosa , Acinetobacter baumannii , Escherichia coli , Klebsiella pneumoniae , and Enterobacter cloacae. dUSTBβP 3 reduced the minimum inhibitory concentration of novobiocin and rifampicin below their interpretative susceptibility breakpoints. Furthermore, compound 3 exhibited improved in vitro stability (86.8 ± 3.7% remaining) relative to its α-amino acid-based counterpart (39.5 ± 7.4% remaining) after a 2 h incubation in human plasma. [ABSTRACT FROM AUTHOR]- Published
- 2021
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26. Genomic and Phenotypic Analysis of Heat and Sanitizer Resistance in Escherichia coli from Beef in Relation to the Locus of Heat Resistance.
- Author
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Xianqin Yang, Frances Tran, Peipei Zhang, and Hui Wang
- Subjects
- *
GENOMICS , *LOCUS (Genetics) , *ESCHERICHIA coli , *LOCUS (Mathematics) , *GENOME size , *PLASMIDS , *ESCHERICHIA coli O157:H7 , *PLASMID genetics - Abstract
The locus of heat resistance (LHR) can confer heat resistance to Escherichia coli to various extents. This study investigated the phylogenetic relationships and the genomic and phenotypic characteristics of E. coli with or without LHR recovered from beef by direct plating or from enrichment broth at 42°C. LHR-positive E. coli isolates (n = 24) were subjected to whole-genome sequencing by short and long reads. LHR-negative isolates (n = 18) from equivalent sources as LHR-positive isolates were short-read sequenced. All isolates were assessed for decimal reduction time at 60°C (D60°C) and susceptibility to the sanitizers E-SAN and Perox-E. Selected isolates were evaluated for growth at 42°C. The LHR-positive and -negative isolates were well separated on the core genome tree, with 22/24 positive isolates clustering into three clades. Isolates within clade 1 and 2, despite their different D60°C values, were clonal, as determined by subtyping (multilocus sequence typing [MLST], core genome MLST, and serotyping). Isolates within each clade are of one serotype. The LHR-negative isolates were genetically diverse. The LHR-positive isolates had a larger (P, 0.001) median genome size by 0.3 Mbp (5.0 versus 4.7 Mbp) and overrepresentation of genes related to plasmid maintenance, stress response, and cryptic prophages but underrepresentation of genes involved in epithelial attachment and virulence. All LHR-positive isolates harbored a chromosomal copy of LHR, and all clade 2 isolates had an additional partial copy of LHR on conjugative plasmids. The growth rates at 42°C were 0.71 6 0.02 and 0.65 6 0.02 log(OD) h21 for LHR-positive and -negative isolates, respectively. No meaningful difference in sanitizer susceptibility was noted between LHR-positive and -negative isolates. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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27. Novobiocin inhibits membrane synthesis and vacuole formation of Enterococcus faecalis protoplasts
- Author
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Rintaro Tsuchikado, Satoshi Kami, Sawako Takahashi, and Hiromi Nishida
- Subjects
bacterial protoplasts/spheroplasts ,dna replication ,enterococcus faecalis ,novobiocin ,plasma membrane synthesis ,vacuole formation ,Biology (General) ,QH301-705.5 - Abstract
We demonstrate that plasma membrane biosynthesis and vacuole formation require DNA replication in Enterococcus faecalis protoplasts. The replication inhibitor novobiocin inhibited not only DNA replication but also cell enlargement (plasma membrane biosynthesis) and vacuole formation during the enlargement of the E. faecalis protoplasts. After novobiocin treatment prior to vacuole formation, the cell size of E. faecalis protoplasts was limited to 6 μm in diameter and the cells lacked vacuoles. When novobiocin was added after vacuole formation, E. faecalis protoplasts grew with vacuole enlargement; after novobiocin removal, protoplasts were enlarged again. Although cell size distribution of the protoplasts was similar following the 24 h and 48 h novobiocin treatments, after 72 h of novobiocin treatment there was a greater number of smaller sized protoplasts, suggesting that extended novobiocin treatment may inhibit the re-enlargement of E. faecalis protoplasts after novobiocin removal. Our findings demonstrate that novobiocin can control the enlargement of E. faecalis protoplasts due to inhibition of DNA replication.
- Published
- 2020
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28. Dioctanoyl Ultrashort Tetrabasic β-Peptides Sensitize Multidrug-Resistant Gram-Negative Bacteria to Novobiocin and Rifampicin
- Author
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Danyel Ramirez, Liam Berry, Ronald Domalaon, Yanqi Li, Gilbert Arthur, Ayush Kumar, and Frank Schweizer
- Subjects
antibiotic adjuvant ,novobiocin ,rifampicin ,peptidomimetic ,β-amino acid ,Pseudomonas aeruginosa ,Microbiology ,QR1-502 - Abstract
Recently reported peptidomimetics with increased resistance to trypsin were shown to sensitize priority multidrug-resistant (MDR) Gram-negative bacteria to novobiocin and rifampicin. To further optimize proteolytic stability, β-amino acid-containing derivatives of these compounds were prepared, resulting in three dioctanoyl ultrashort tetrabasic β-peptides (dUSTBβPs). The nonhemolytic dUSTBβP 3, comprised of three β3-homoarginine residues and two fatty acyl tails eight carbons long, enhanced the antibacterial activity of various antibiotics from different classes. Notably, compound 3 retained the ability to potentiate novobiocin and rifampicin in wild-type Gram-negative bacteria against MDR clinical isolates of Pseudomonas aeruginosa, Acinetobacter baumannii, Escherichia coli, Klebsiella pneumoniae, and Enterobacter cloacae. dUSTBβP 3 reduced the minimum inhibitory concentration of novobiocin and rifampicin below their interpretative susceptibility breakpoints. Furthermore, compound 3 exhibited improved in vitro stability (86.8 ± 3.7% remaining) relative to its α-amino acid-based counterpart (39.5 ± 7.4% remaining) after a 2 h incubation in human plasma.
- Published
- 2021
- Full Text
- View/download PDF
29. Efficacy of Treatment with the Antibiotic Novobiocin against Infection with Bacillus anthracis or Burkholderia pseudomallei
- Author
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Christopher P. Klimko, Susan L. Welkos, Jennifer L. Shoe, Sherry Mou, Melissa Hunter, Nathaniel O. Rill, David DeShazer, and Christopher K. Cote
- Subjects
Burkholderia pseudomallei ,Bacillus anthracis ,novobiocin ,early-generation antibiotics ,broad spectrum ,biothreats ,Therapeutics. Pharmacology ,RM1-950 - Abstract
The microbial pathogens Burkholderia pseudomallei and Bacillus anthracis are unrelated bacteria, yet both are the etiologic agents of naturally occurring diseases in animals and humans and are classified as Tier 1 potential biothreat agents. B. pseudomallei is the gram-negative bacterial agent of melioidosis, a major cause of sepsis and mortality globally in endemic tropical and subtropical regions. B. anthracis is the gram-positive spore-forming bacterium that causes anthrax. Infections acquired by inhalation of these pathogens are challenging to detect early while the prognosis is best; and they possess innate multiple antibiotic resistance or are amenable to engineered resistance. Previous studies showed that the early generation, rarely used aminocoumarin novobiocin was very effective in vitro against a range of highly disparate biothreat agents. The objective of the current research was to begin to characterize the therapeutic efficacy of novobiocin in mouse models of anthrax and melioidosis. The antibiotic was highly efficacious against infections by both pathogens, especially B. pseudomallei. Our results supported the concept that specific older generation antimicrobials can be effective countermeasures against infection by bacterial biothreat agents. Finally, novobiocin was shown to be a potential candidate for inclusion in a combined pre-exposure vaccination and post-exposure treatment strategy designed to target bacterial pathogens refractory to a single medical countermeasure.
- Published
- 2022
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30. Overcoming Therapeutic Challenges of Antibiotic Delivery with Cubosome Lipid Nanocarriers.
- Author
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Dyett BP, Sarkar S, Yu H, Strachan J, Drummond CJ, and Conn CE
- Subjects
- Nanoparticles chemistry, Microbial Sensitivity Tests, Humans, Drug Delivery Systems, Anti-Bacterial Agents chemistry, Anti-Bacterial Agents pharmacology, Pseudomonas aeruginosa drug effects, Drug Carriers chemistry, Lipids chemistry
- Abstract
Low discovery rates for new antibiotics, commercial disincentives to invest, and inappropriate use of existing drugs have created a perfect storm of antimicrobial resistance (AMR). This "silent pandemic" of AMR looms as an immense, global threat to human health. In tandem, many potential novel drug candidates are not progressed due to elevated hydrophobicity, which may result in poor intracellular internalization and undesirable serum protein binding. With a reducing arsenal of effective antibiotics, enabling technology platforms that improve the outcome of treatments, such as repurposing existing bioactive agents, is a prospective option. Nanocarrier (NC) mediated drug delivery is one avenue for amplifying the therapeutic outcome. Here, the performance of several antibiotic classes encapsulated within the lipid-based cubosomes is examined. The findings demonstrate that encapsulation affords significant improvements in drug concentration:inhibition outcomes and assists in other therapeutic challenges associated with internalization, enzyme degradation, and protein binding. We emphasize that a currently sidelined compound, novobiocin, became active and revealed a significant increase in inhibition against the pathogenic Gram-negative strain, Pseudomonas aeruginosa . Encapsulation affords co-delivery of multiple bioactives as a strategy for mitigating failure of monotherapies and tackling resistance. The rationale in optimized drug selection and nanocarrier choice is examined by transport modeling which agrees with experimental inhibition results. The results demonstrate that lipid nanocarrier encapsulation may alleviate a range of challenges faced by antibiotic therapies and increase the range of antibiotics available to treat bacterial infections.
- Published
- 2024
- Full Text
- View/download PDF
31. POLQ inhibition attenuates the stemness and ferroptosis resistance in gastric cancer cells via downregulation of dihydroorotate dehydrogenase.
- Author
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Peng Y, Zheng W, Chen Y, Lei X, Yang Z, Yang Y, Liang W, Sun K, Li G, and Yu J
- Subjects
- Humans, Cell Line, Tumor, Dihydroorotate Dehydrogenase, Down-Regulation genetics, Novobiocin, Ferroptosis genetics, Stomach Neoplasms drug therapy, Stomach Neoplasms genetics
- Abstract
Gastric cancer (GC) contains subpopulations of cancer stem cells (CSCs), which are described as the main contributors in tumor initiation and metastasis. It is necessary to clarify the molecular mechanism underlying CSCs phenotype and develop novel biomarkers and therapeutic targets for gastric cancer. Here, we show that POLQ positively regulates stem cell-like characteristics of gastric cancer cells, knockdown of POLQ suppressed the stemness of GC cells in vitro and in vivo. Further mechanistic studies revealed that POLQ knockdown could downregulate the expression of dihydroorotate dehydrogenase (DHODH). DHODH overexpression rescued the reduced stemness resulted by POLQ knockdown. Furthermore, we found that POLQ expression correlated with resistance to ferroptosis, and POLQ inhibition renders gastric cancer cells more vulnerable to ferroptosis. Further investigation revealed that POLQ regulated DHODH expression via the transcription factors E2F4, thereby regulating ferroptosis resistance and stemness of gastric cancer cells. Given the importance of POLQ in stemness and ferroptosis resistance of GC, we further evaluated the therapeutic potential of POLQ inhibitor novobiocin, the results show that novobiocin attenuates the stemness of GC cells and increased ferroptosis sensitivity. Moreover, the combination of POLQ inhibitor and ferroptosis inducer synergistically suppressed MGC-803 xenograft tumor growth and diminished metastasis. Our results identify a POLQ-mediated stemness and ferroptosis defense mechanism and provide a new therapeutic strategy for gastric cancer., (© 2024. The Author(s).)
- Published
- 2024
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32. Antimicrobial susceptibility of mastitis pathogens isolated from North American dairy cattle, 2011-2022.
- Author
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Sweeney MT, Gunnett L, Kumar DM, Lunt BL, Moulin V, Barrett M, Gurjar A, Doré E, Pedraza JR, Bade D, and Machin C
- Subjects
- Female, Cattle, Animals, Staphylococcus aureus, Escherichia coli, Cefoperazone, Novobiocin, Microbial Sensitivity Tests veterinary, Drug Resistance, Bacterial, Anti-Bacterial Agents pharmacology, North America, Erythromycin, Ampicillin, Oxacillin, Anti-Infective Agents, Mastitis, Bovine epidemiology, Mastitis, Bovine microbiology, Cattle Diseases, Cephalosporins
- Abstract
A total of 10,890 bacterial isolates of Streptococcus dysgalactiae, Streptococcus uberis, Staphylococcus aureus and Escherichia coli isolated as etiological agents from dairy cows with mastitis by 29 veterinary laboratories across North America between 2011 and 2022 were tested for in vitro antimicrobial susceptibility by broth microdilution to ampicillin, cefoperazone, ceftiofur, cephalothin, erythromycin, oxacillin, penicillin-novobiocin and pirlimycin according to CLSI standards. Using available clinical breakpoints, antimicrobial resistance among S. dysgalactiae (n = 2406) was low for penicillin-novobiocin (0% resistance), ceftiofur (0.1%), erythromycin (3.2%) and pirlimycin (4.6%). Among S. uberis (n = 2398), resistance was low for ampicillin (0%) and ceftiofur (0.2%) and moderate for erythromycin (11.9%) and pirlimycin (18.4%). For S. aureus (n = 3194), resistance was low for penicillin-novobiocin (0%), ceftiofur (0.1%), oxacillin (0.2%), erythromycin (0.7%), cefoperazone (1.2%) and pirlimycin (2.8%). For E. coli (n = 2892), resistance was low for ceftiofur (2.8%) and cefoperazone (3.4%) and moderate for ampicillin (9.2%). Overall, the results indicate that mastitis pathogens in the United States and Canada have not shown any substantial changes in the in vitro susceptibility to antimicrobial drugs over the 12 years of the study, or among that of the proceeding survey from 2002-2010. The data support the conclusion that resistance to common antimicrobial drugs among mastitis pathogens, even to drugs that have been used in dairies for mastitis management for many years, continues to remain low., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)
- Published
- 2024
- Full Text
- View/download PDF
33. Properties of AdeABC and AdeIJK Efflux Systems of Acinetobacter baumannii Compared with Those of the AcrAB-TolC System of Escherichia coli
- Author
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Sugawara, Etsuko and Nikaido, Hiroshi
- Subjects
Antimicrobial Resistance ,Biodefense ,Vaccine Related ,Prevention ,Acinetobacter baumannii ,Anti-Bacterial Agents ,Bacterial Outer Membrane Proteins ,Bacterial Proteins ,Drug Resistance ,Multiple ,Bacterial ,Erythromycin ,Escherichia coli ,Escherichia coli Proteins ,Ethidium ,Gene Expression Regulation ,Bacterial ,Genetic Complementation Test ,Lipoproteins ,Membrane Transport Proteins ,Microbial Sensitivity Tests ,Multidrug Resistance-Associated Proteins ,Novobiocin ,Recombinant Proteins ,Tetracycline ,beta-Lactamases ,beta-Lactams ,Microbiology ,Medical Microbiology ,Pharmacology and Pharmaceutical Sciences - Abstract
Acinetobacter baumannii contains RND-family efflux systems AdeABC and AdeIJK, which pump out a wide range of antimicrobial compounds, as judged from the MIC changes occurring upon deletion of the responsible genes. However, these studies may miss changes because of the high backgrounds generated by the remaining pumps and by β-lactamases, and it is unclear how the activities of these pumps compare quantitatively with those of the well-studied AcrAB-TolC system of Escherichia coli. We expressed adeABC and adeIJK of A. baumannii, as well as E. coli acrAB, in an E. coli host from which acrAB was deleted. The A. baumannii pumps were functional in E. coli, and the MIC changes that were observed largely confirmed the substrate range already reported, with important differences. Thus, the AdeABC system pumped out all β-lactams, an activity that was often missed in deletion studies. When the expression level of the pump genes was adjusted to a similar level for a comparison with AcrAB-TolC, we found that both A. baumannii efflux systems pumped out a wide range of compounds, but AdeABC was less effective than AcrAB-TolC in the extrusion of lipophilic β-lactams, novobiocin, and ethidium bromide, although it was more effective at tetracycline efflux. AdeIJK was remarkably more effective than a similar level of AcrAB-TolC in the efflux of β-lactams, novobiocin, and ethidium bromide, although it was less so in the efflux of erythromycin. These results thus allow us to compare these efflux systems on a quantitative basis, if we can assume that the heterologous systems are fully functional in the E. coli host.
- Published
- 2014
34. Disparate outer membrane exclusionary properties underlie intrinsic resistance to hydrophobic substances in Pseudomonas spp. isolated from surface waters under triclosan selection.
- Author
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Chambers, Lauren E., Chang, Mang, Boyina, Kavya, Williams, Ashton, Dye, Rebecca, Miller, Robert V., DeGear, Michelle A., Assefa, Senait, Köhler, Gerwald A., and Champlin, Franklin R.
- Subjects
- *
TRICLOSAN , *PSEUDOMONAS , *ANTIBACTERIAL agents , *FLUORESCENT probes , *RNA sequencing , *MUNICIPAL water supply - Abstract
Representative members of surface water microbiota were obtained from three unrelated municipal sites in Oklahoma by direct plating under selection by the hydrophobic biocide triclosan. Multiple methods were employed to determine if intrinsic triclosan resistance reflected resistance to hydrophobic molecules by virtue of outer membrane impermeability. While all but one organism isolated in the absence of triclosan were able to initiate growth on MacConkey agar, only one was able to initiate significant growth with triclosan present. In contrast, all bacteria selected with triclosan were identified as Pseudomonas spp. using 16S RNA gene sequencing and exhibited growth comparable to Pseudomonas aeruginosa controls in the presence of hydrophobic antibacterial agents to include triclosan. Two representative bacteria isolated in the absence of triclosan allowed for greater outer membrane association with the fluorescent hydrophobic probe 1-N-phenylnapthylamine than did two triclosan-resistant isolates. Compound 48/80 disruption of outer membrane impermeability properties for hydrophobic substances either partially or fully sensitized nine of twelve intrinsically resistant isolates to triclosan. These data suggest that outer membrane exclusion underlies intrinsic resistance to triclosan in some, but not all Pseudomonas spp. isolated by selection from municipal surface waters and implicates the involvement of concomitant triclosan resistance mechanisms. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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- View/download PDF
35. Proposal of Thermoactinomyces mirandus sp. nov., a filamentous, anaerobic bacterium isolated from a biogas plant.
- Author
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Mutschlechner, Mira, Lackner, Nina, Markt, Rudolf, Salvenmoser, Willi, Dunlap, Christopher A., and Wagner, Andreas O.
- Abstract
We isolated a filamentous, thermophilic, and first anaerobic representative of the genus Thermoactinomyces, designated strain AMNI-1
T , from a biogas plant in Tyrol, Austria and report the results of a phenotypic, genetic, and phylogenetic investigation. Strain AMNI-1T was observed to form a white branching mycelium that aggregates into pellets when grown in liquid medium. Cells could primarily utilize lactose, glucose, and mannose as carbon and energy sources, with acetate accelerating and yeast extract being mandatory for growth. The optimum growth temperature and pH turned out to be 55 °C and pH 7.0, respectively, with an optimum NaCl concentration of 0–2% (w/v). 16S rRNA gene sequence comparison indicated that the genetic relatedness between strain AMNI-1T and Thermoactinomyces intermedius, Thermoactinomyces khenchelensis, and Thermoactinomyces vulgaris was less than 97%. The G + C content of the genomic DNA was 44.7 mol%. The data obtained suggest that the isolate represents a novel and first anaerobic species of the genus Thermoactinomyces, for which the name Thermoactinomyces mirandus is proposed. The type strain is AMNI-1T (= DSM 110094T = LMG 31503T ). The description of the genus Thermoactinomyces is emended accordingly. [ABSTRACT FROM AUTHOR]- Published
- 2021
- Full Text
- View/download PDF
36. Effects of Lysine N-ζ-Methylation in Ultrashort Tetrabasic Lipopeptides (UTBLPs) on the Potentiation of Rifampicin, Novobiocin, and Niclosamide in Gram-Negative Bacteria
- Author
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Linus Schweizer, Danyel Ramirez, and Frank Schweizer
- Subjects
outer membrane permeabilizer ,antibiotic potentiator ,antibiotic adjuvant ,novobiocin ,rifampicin ,niclosamide ,Therapeutics. Pharmacology ,RM1-950 - Abstract
Outer membrane (OM) drug impermeability typically associated with a molecular weight above 600 Da and high hydrophobicity prevents accumulation of many antibiotics in Gram-negative bacteria (GNB). Previous studies have shown that ultrashort tetrabasic lipopeptides (UTBLPs) containing multiple lysine residues potentiate Gram-positive bacteria (GPB)-selective antibiotics in GNB by enhancing OM permeability. However, there is no available information on how N-substitution at the ζ-position of lysine in UTBLPs affects antibiotic potentiation in GNB. To study these effects, we prepared a series of branched and linear UTBLPs that differ in the degree of N-ζ-methylation and studied their potentiating effects with GPB-selective antibiotics including rifampicin, novobiocin, niclosamide, and chloramphenicol against wild-type and multidrug-resistant GNB isolates. Our results show that increasing N-ζ-methylation reduces or abolishes the potentiating effects of UTBLPs with rifampicin, novobiocin, and niclosamide against GNB. No trend was observed with chloramphenicol that is largely affected by efflux. We were unable to observe a correlation between the strength of the antibiotic potentiating effect to the increase in fluorescence in the 1-N-phenylnaphthylamine (NPN) OM permeability assay suggesting that other factors besides OM permeability of NPN play a role in antibiotic potentiation. In conclusion, our study has elucidated crucial structure–activity relationships for the optimization of polybasic antibiotic potentiators in GNB.
- Published
- 2022
- Full Text
- View/download PDF
37. Usefulness of novobiocin as a selective inhibitor of intestinal breast cancer resistance protein (Bcrp) in rats.
- Author
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Suzuki, Kei, Taniyama, Kazuhiro, Aoyama, Takao, and Watanabe, Yoshiaki
- Subjects
- *
INTESTINAL cancer , *SPRAGUE Dawley rats , *BREAST cancer , *INTESTINAL absorption , *RATS , *ION transport (Biology) - Abstract
We investigated whether novobiocin is useful for elucidating the contribution of breast cancer resistance protein (Bcrp) to intestinal absorption without affecting the activities of P-glycoprotein (P-gp), cytochrome P450 (CYP) 3 A and hepatic organic anion transporting polypeptide (Oatp) in rats. To determine the effects of novobiocin on Bcrp, P-gp, CYP3A and Oatp activities, we used sulfasalazine, fexofenadine, bosentan and midazolam, respectively, as probe substrates. Each substrate was orally or intravenously administered to rats 15 min after oral novobiocin administration at a dose of 3 mg/kg. Pre-treatment with novobiocin significantly increased the area under the plasma concentration–time curve and the peak plasma concentration of sulfasalazine after oral administration by 3.2- and 5.9-fold, respectively, in rats, whereas its systemic clearance following intravenous dosing was not influenced. These results indicate that novobiocin selectively inhibits intestinal Bcrp-mediated efflux with limited effects on extra-intestinal Bcrp activity. In addition, novobiocin pre-treatment did not significantly alter the pharmacokinetic parameters of orally administered fexofenadine and midazolam or intravenously administered bosentan, suggesting that the effects of novobiocin on other processes were negligible. These findings demonstrate that novobiocin permits estimating the net contribution of Bcrp to intestinal absorption of drug candidates. [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
- View/download PDF
38. Inhibition of indole production increases the activity of quinolone antibiotics against E. coli persisters.
- Author
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Zarkan, Ashraf, Matuszewska, Marta, Trigg, Stephen B., Zhang, Meng, Belgami, Daaniyah, Croft, Cameron, Liu, Junyan, El-Ouisi, Sawssen, Greenhalgh, Jack, Duboff, James S., Rahman, Taufiq, and Summers, David K.
- Subjects
- *
QUINOLONE antibacterial agents , *ESCHERICHIA coli , *DNA topoisomerase II , *MOLECULAR docking , *NOVOBIOCIN - Abstract
Persisters are a sub-population of genetically sensitive bacteria that survive antibiotic treatment by entering a dormant state. The emergence of persisters from dormancy after antibiotic withdrawal leads to recurrent infection. Indole is an aromatic molecule with diverse signalling roles, including a role in persister formation. Here we demonstrate that indole stimulates the formation of Escherichia coli persisters against quinolone antibiotics which target the GyrA subunit of DNA gyrase. However, indole has no effect on the formation of E. coli persisters against an aminocoumarin, novobiocin, which targets the GyrB subunit of DNA gyrase. Two modes of indole signalling have been described: persistent and pulse. The latter refers to the brief but intense elevation of intracellular indole during stationary phase entry. We show that the stimulation of quinolone persisters is due to indole pulse, rather than persistent, signalling. In silico docking of indole on DNA gyrase predicts that indole docks perfectly to the ATP binding site of the GyrB subunit. We propose that the inhibition of indole production offers a potential route to enhance the activity of quinolones against E. coli persisters. [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
- View/download PDF
39. Genetic and Chemical Screening Reveals Targets and Compounds to Potentiate Gram-Positive Antibiotics against Gram-Negative Bacteria
- Author
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Kristina Klobucar, Emily Jardine, Maya A. Farha, Marc R. MacKinnon, Meghan Fragis, Brenda Nkonge, Timsy Bhando, Louis Borrillo, Caressa N. Tsai, Jarrod W. Johnson, Brian K. Coombes, Jakob Magolan, and Eric D. Brown
- Subjects
Lipid A ,Infectious Diseases ,Vancomycin ,Gram-Negative Bacteria ,Linezolid ,Rifampin ,Novobiocin ,Oxazolidinones ,Anti-Bacterial Agents ,Erythromycin - Abstract
Gram-negative bacteria are intrinsically resistant to a plethora of antibiotics that effectively inhibit the growth of Gram-positive bacteria. The intrinsic resistance of Gram-negative bacteria to classes of antibiotics, including rifamycins, aminocoumarins, macrolides, glycopeptides, and oxazolidinones, has largely been attributed to their lack of accumulation within cells due to poor permeability across the outer membrane, susceptibility to efflux pumps, or a combination of these factors. Due to the difficulty in discovering antibiotics that can bypass these barriers, finding targets and compounds that increase the activity of these ineffective antibiotics against Gram-negative bacteria has the potential to expand the antibiotic spectrum. In this study, we investigated the genetic determinants for resistance to rifampicin, novobiocin, erythromycin, vancomycin, and linezolid to determine potential targets of antibiotic-potentiating compounds. We subsequently performed a high-throughput screen of ∼50,000 diverse, synthetic compounds to uncover molecules that potentiate the activity of at least one of the five Gram-positive-targeting antibiotics. This led to the discovery of two membrane active compounds capable of potentiating linezolid and an inhibitor of lipid A biosynthesis capable of potentiating rifampicin and vancomycin. Furthermore, we characterized the ability of known inhibitors of lipid A biosynthesis to potentiate the activity of rifampicin against Gram-negative pathogens.
- Published
- 2022
40. A novobiocin derivative, XN4, triggers ferroptosis in gastric cancer cells via the activation of NOX4
- Author
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Rongrong, Li, Bin, Yin, Deyu, Zeng, and Zhenyang, Liu
- Subjects
Pharmacology ,Cell Death ,Pharmaceutical Science ,Apoptosis ,General Medicine ,Complementary and alternative medicine ,NADPH Oxidase 4 ,Stomach Neoplasms ,Drug Discovery ,Ferroptosis ,Humans ,Molecular Medicine ,Lipid Peroxidation ,Reactive Oxygen Species ,Novobiocin - Abstract
A novobiocin derivative, XN4, has been shown to promote cell apoptosis in chronic myeloid leukaemia.This study explores the mechanism by which XN4 promotes ferroptosis of gastric cancer (GC) cells.Human GC SGC-7901 and BGC-823 cells were treated with different XN4 concentrations (0, 0.1, 0.5, 1.0, 5.0, and 10.0 μmol/L) to evaluate effects of XN4. Additionally, cells were pre-treated for 24 h with si-NOX4, for 1 h with the iron chelator deferoxamine mesylate (DFO) or for 1 h with the lipid peroxidation inhibitor liproxstatin-1 before being treated with XN4 to analyse the mechanism of XN4.XN4 increased cell death (ICThe pro-ferroptotic role of XN4 in GC might enable it to become a promising drug for GC treatment in the future despite the need for extensive research.
- Published
- 2022
41. Antibacterial potential of Thymus linearis essential oil collected from Wasturwan mountain: A combination of experimental and theoretical studies involving in silico molecular docking simulation of the major compounds against Novobiocin-resistant mutant of DNA Gyrase-B.
- Author
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Firdous S, Bhat SH, Aziz S, Jehangir M, Syeed S, Iqra Z, Ahmad MA, Rasool S, Khursheed A, Shalla AH, Ganaie AA, and Rather MA
- Subjects
- Thymol, Molecular Docking Simulation, DNA Gyrase, Novobiocin, Anti-Bacterial Agents pharmacology, Oils, Volatile pharmacology, Oils, Volatile chemistry, Thymus Plant
- Abstract
Antibiotic resistant bacteria are immune to most antibiotics and are therefore very difficult to treat and in most cases lead to death. As such there is a pressing need for alternative and more efficient antibacterial drugs which can target these drug-resistant strains as well. The objective of this research work was to investigate the antibacterial properties of Thymus linearis essential oil (EO) against multiple disease-causing bacterial pathogens. Additionally, the study aimed to examine the molecular docking and molecular dynamic (MD) simulations of the primary components of the EO with the essential bacterial proteins and enzymes. Gas chromatography-mass spectrometry was employed to analyse the chemical composition of Thymus linearis EO. The initial screening for antibacterial properties involved the use of disc diffusion and microdilution techniques. Molecular docking studies were conducted utilising Autodock Vina. The outcomes were subsequently visualised through BIOVIA Discovery Studio. MD simulations were conducted using iMODS, an internet-based platform designed for MD simulations. The essential oil (EO) was found to contain 26 components, with thymol, carvacrol, p-cymene, and γ-terpinene being the primary constituents. The study findings revealed that Thymus linearis EO demonstrated antibacterial effects that were dependent on both the dose and time. The results of molecular docking studies revealed that the primary constituents of the EO, namely thymol, carvacrol, and p-cymene, exhibited robust interactions with the active site of the bacterial DNA gyrase enzyme. This finding provides an explanation for the antibacterial mechanism of the EO. The results indicate that Thymus linearis EO possesses potent antibacterial properties against the MDR microorganisms. Molecular docking analyses revealed that the essential oil's primary components interact with the amino acid residues of the DNA-Gyrase B enzyme, resulting in a favourable docking score., Competing Interests: Declaration of competing interest The authors declare that there is no conflict of interest to indicate., (Copyright © 2023. Published by Elsevier Ltd.)
- Published
- 2023
- Full Text
- View/download PDF
42. Novobiocin, a Newly Found TRPV1 Inhibitor, Attenuates the Expression of TRPV1 in Rat Intestine and Intestinal Epithelial Cell Line IEC-6
- Author
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Qianying Liang, Xueli Lv, Qing Cai, Yun Cai, Boxin Zhao, and Guofeng Li
- Subjects
novobiocin ,capsaicin ,TRPV1 ,inhibitor ,expression ,Therapeutics. Pharmacology ,RM1-950 - Abstract
Background and Purpose: Novobiocin (NOVO), an ABC transporter inhibitor, decreases intestinal wall permeability of capsaicin (CAP), an ABC transporter substrate. However, the mechanism of this effect is not consistent with the action of NOVO as an ABC transporter inhibitor. We previously found that CAP can also be transported via TRPV1, which was site-specific in the permeability of CAP across the intestine. We explored the regulation by NOVO of TRPV1 in the present study.Methods: Rats and transfected IEC-6 cells were used as the models to assess intestinal permeability and expression of TRPV1. Ussing chamber and intracellular accumulation were used to evaluate the influence of NOVO on the transport of CAP in vitro. The expression of TRPV1 was detected after administration of NOVO by qRT-PCR, western blot and immunofluorescent imaging. In addition, MTT and lactate dehydrogenase (LDH) were used to evaluate the cytotoxicity of NOVO in both rat and cell models. Finally, the effect of NOVO on the absorption of CAP in vivo was studied by LC-MS/MS.Results:In vitro data showed that there existed a dose-dependent relationship in the range of concentration between 5 and 50 μM, and even 5 μM NOVO could decrease intestinal permeability of CAP across the intestine. Meanwhile, cytosolic accumulation of CAP decreased when NOVO was used simultaneously or 24 h in advance. NOVO exhibited an inhibition level similar to that of ruthenium red (RR) or SB-705498, a TRPV1-specific inhibitor. NOVO down-regulated TRPV1 expression in the intestine and in transfected cells in a concentration-dependent fashion, hinting that its inhibition of the permeability of CAP is due to its inhibition of TRPV1 expression. Immunofluorescent imaging data showed that the fluorescence intensity of TRPV1 was reduced after pre-treatment with NOVO and SB-705498. In vivo data further demonstrated that oral co-administration of NOVO decreased Cmax and AUC of CAP in dosage-dependent ways, consistent with its role as a TRPV1 inhibitor.Conclusion: NOVO could be a potential TRPV1 inhibitor by attenuating the expression of TRPV1 and may be used to attenuate permeability of TRPV1 substrates.
- Published
- 2018
- Full Text
- View/download PDF
43. StaR Is a Positive Regulator of Topoisomerase I Activity Involved in Supercoiling Maintenance in Streptococcus pneumoniae
- Author
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Antonio A. de Vasconcelos Junior, Jose M. Tirado-Vélez, Antonio J. Martín-Galiano, Diego Megias, María-José Ferrándiz, Pablo Hernández, Mónica Amblar, Adela G. de la Campa, Agencia Estatal de Investigación (España), Ministerio de Economía e Innovación (España), and Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF)
- Subjects
DNA, Bacterial ,StaR ,Supercoiling homeostasis ,Organic Chemistry ,Nucleoid-associated proteins ,DNA gyrase ,General Medicine ,DNA supercoiling ,Catalysis ,Supercoiling regulation ,Computer Science Applications ,DNA topoisomerase I ,supercoiling regulation ,supercoiling homeostasis ,nucleoid-associated proteins ,topsoisomerase regulator ,Inorganic Chemistry ,Streptococcus pneumoniae ,DNA Topoisomerases, Type I ,Topsoisomerase regulator ,Humans ,Physical and Theoretical Chemistry ,Molecular Biology ,Novobiocin ,Spectroscopy - Abstract
The DNA topoisomerases gyrase and topoisomerase I as well as the nucleoid-associated protein HU maintain supercoiling levels in Streptococcus pneumoniae, a main human pathogen. Here, we characterized, for the first time, a topoisomerase I regulator protein (StaR). In the presence of sub-inhibitory novobiocin concentrations, which inhibit gyrase activity, higher doubling times were observed in a strain lacking staR, and in two strains in which StaR was over-expressed either under the control of the ZnSO4-inducible PZn promoter (strain ΔstaRPZnstaR) or of the maltose-inducible PMal promoter (strain ΔstaRpLS1ROMstaR). These results suggest that StaR has a direct role in novobiocin susceptibility and that the StaR level needs to be maintained within a narrow range. Treatment of ΔstaRPZnstaR with inhibitory novobiocin concentrations resulted in a change of the negative DNA supercoiling density (σ) in vivo, which was higher in the absence of StaR (σ = −0.049) than when StaR was overproduced (σ = −0.045). We have located this protein in the nucleoid by using super-resolution confocal microscopy. Through in vitro activity assays, we demonstrated that StaR stimulates TopoI relaxation activity, while it has no effect on gyrase activity. Interaction between TopoI and StaR was detected both in vitro and in vivo by co-immunoprecipitation. No alteration of the transcriptome was associated with StaR amount variation. The results suggest that StaR is a new streptococcal nucleoid-associated protein that activates topoisomerase I activity by direct protein-protein interaction.
- Published
- 2023
44. PREVALENCE OF ANTIBIOTIC RESISTANCE IN THE BACTERIAL ISOLATES SOURCED FROM DISEASED FISH OF DIFFERENT ENVIRONMENTAL CONDITIONS OF SUB HIMALAYAN REGIONS.
- Author
-
G., Suneeta and Prasad, Yogendra
- Subjects
AEROMONAS hydrophila ,AQUACULTURE ,DRUG resistance ,NOVOBIOCIN ,SEPSIS - Abstract
This study was conducted to know the prevalence of antibiotic resistance among the isolates of A. hydrophila of different ecological conditions viz. a reservoir (Nanak Sagar, UK), river (Nakatia at Bareilly fed with the Himalayan rivers) and fish stocking ponds (Puranpur fish hatchery) found persistently associated with diseased Labeo rohita, Cirrhinus mrigala, Calta catla and Cyprinus carpio with explicit symptoms of haemorrhagic septicaemia (BHS). Out of 28 isolates of bacteria isolated on Rimler Shotts (RS) medium followed by MacConkey agar, AIA and Nutrient agar (Hi Media, Mumbai) and subjected to physical (temp. pH and salinity), biochemical tests (positive response to oxidase, catalase, gelatin, nitrate utilization, H2S production, Indole, VP reaction, oxidative fermentative tests, blood agar, citrate and negative to methyle red and urease), 15 isolates (54%) were confirmed as A. hydrophila along with ATCC 7966. There were variations in the antibiotic resistance pattern (checked using octadiscs of 23 antibiotics) as the very few (20%) isolates of A. hydrophila of fish of Nanak Sagar exhibited mild to moderate resistance to novobiocin, amoxyclave whereas the 100% isolates of Nakatia river found to be resistant to novobiocin, amoxyclave followed by ampicillin, co-trimoxazole (90%), sulphatrid, teioplanin, co-trimazine, co-trimoxazole -sulpha/trimethoprim (80%), colistin sulphate (60%), cephalothin, nitrofurantoin, tetracyclin (40%), streptomycin, gentamicin, netillin and ceftriaxone (20%). Interestingly, majority of the isolates of Puranpur fish hatchery were resistant to novobiocin, amoxyclave, ampicillin, sulphatrid and teioplanin. None of the isolates exhibited resistance to amikacin, kanamycin, carbenicillin, levofloxacin, ofloxacin, chloramphenicol and ciprofloxacin. It can be concluded that A. hydrophila of varied environmental conditions showed different pattern of antibiotic resistance, more in reverine and hatchery systems and less in reservoir. If it prevails there may be the chance of gene transfer among other groups of bacteria which may prove to be fatal to aquaculture industries of Sub Himalayan regions. [ABSTRACT FROM AUTHOR]
- Published
- 2019
- Full Text
- View/download PDF
45. Novobiocin-ferrocene conjugates possessing anticancer and antiplasmodial activity independent of HSP90 inhibition.
- Author
-
Mbaba, Mziyanda, de la Mare, Jo-Anne, Sterrenberg, Jason N., Kajewole, Deborah, Maharaj, Shantal, Edkins, Adrienne L., Isaacs, Michelle, Hoppe, Heinrich C., and Khanye, Setshaba D.
- Subjects
- *
NOVOBIOCIN , *FERROCENE , *HEAT shock proteins , *ANTINEOPLASTIC agents , *ANTIMALARIALS , *BREAST cancer treatment - Abstract
Abstract: A series of tailored novobiocin-ferrocene conjugates was prepared in moderate yields and investigated for in vitro anticancer and antiplasmodial activity against the MDA-MB-231 breast cancer line and Plasmodium falciparum 3D7 strain, respectively. While the target compounds displayed moderate anticancer activity against the breast cancer cell line with IC50 values in the mid-micromolar range, compounds 10a-c displayed promising antiplasmodial activity as low as 0.889 µM. Furthermore, the most promising compounds were tested for inhibitory effects against a postulated target, heat shock protein 90 (Hsp90).Graphical abstract: A selection of tailored novobiocin derivatives bearing the organometallic ferrocene unit were synthesized and characterized by common spectroscopic techniques. The target compounds were investigated for in vitro anticancer and antimalarial activity against the MDA-MB-231 breast cancer cell line and Plasmodium falciparum 3D7 strain, respectively. [ABSTRACT FROM AUTHOR]
- Published
- 2019
- Full Text
- View/download PDF
46. Incidence and antimicrobial susceptibility of Staphylococcus aureus isolated from ready-to-eat foods of animal origin from tourist destinations of North-western Himalayas, Himachal Pradesh, India.
- Author
-
Lakhanpal, Priyanka, Panda, Ashok Kumar, Chahota, Rajesh, Choudhary, Shivani, and Thakur, Sidharath Dev
- Abstract
This study was aimed to determine the incidence of Staphylococcus aureus in ready-to-eat (RTE) milk (n = 120) and meat (n = 120) products from various tourist places in north western Himalayas, Himachal Pradesh, India. S. aureus isolates and its enterotoxins; A, B, D and E were characterized by conventional and molecular methods. Antimicrobial susceptibility (AMS) profiles of S. aureus isolates were determined by disk diffusion method using Clinical and Laboratory Standards Institute criteria. Overall, 6.7% (n = 16/240) food samples were positive for S. aureus. PCR amplification of nucA confirmed all biochemically characterized isolates as S. aureus. Incidence of S. aureus was higher (10.0%) in RTE milk products than meat products (3.3%). S. aureus contamination levels were highest in milk cake/khoa (26.0%, p = 0.0002) followed by ice cream/kulfi (10.0%, p = 0.4), mutton momo (10.0%, p = 0.4), burfi (3.3%, p = 0.7) and chicken momo (3.3%, p = 0.7). None of the isolates carried genes for S. aureus enterotoxins; A, B, D and E. AMS testing revealed seven different resistance patterns and 81.3% multi drug resistance. All the isolates were resistant to ampicillin. High resistance levels were observed against methicillin (93.7%), clindamycin (68.8%), erythromycin (56.3%) and vancomycin (43.8%). Vancomycin resistant (n = 7) isolates were also resistant to methicillin. All isolates were susceptible to novobiocin. [ABSTRACT FROM AUTHOR]
- Published
- 2019
- Full Text
- View/download PDF
47. Proposal of a novel selective enrichment broth, NCT-mTSB, for isolation of Escherichia albertii from poultry samples
- Author
-
Yuki Wakabayashi, Kazuko Seto, Kentaro Kawatsu, Masashi Kanki, and Tetsuya Harada
- Subjects
Escherichia ,food.ingredient ,Protein Hydrolysates ,medicine.disease_cause ,Applied Microbiology and Biotechnology ,Poultry ,Tryptic soy broth ,Escherichia albertii ,chemistry.chemical_compound ,food ,Cefixime ,medicine ,Animals ,Agar ,Shigella ,Food science ,Escherichia coli ,Novobiocin ,biology ,Caseins ,General Medicine ,biology.organism_classification ,Enterobacteriaceae ,Culture Media ,chemistry ,Food Microbiology ,Tellurium ,Bacteria ,Biotechnology ,medicine.drug - Abstract
Aims Escherichia albertii is an emerging diarrheagenic pathogen causing food- and water-borne infection in humans. However, no selective enrichment broths for E. albertii have ever been reported. In this study, we tested several basal media, selective supplements and culture conditions which enabled selective enrichment of E. albertii. Methods and Results We developed a selective enrichment broth, novobiocin–cefixime–tellurite supplemented modified tryptic soy broth (NCT-mTSB). NCT-mTSB supported the growth of 22 E. albertii strains, while inhibited growth of other Enterobacteriaceae at 37°C, except for Escherichia coli and Shigella spp. Enrichment of E. albertii was improved further by growth at 44°C, a temperature that suppresses growth of several strains of E. coli/Shigella. Combined use of NCT-mTSB with XR-DH-agar, xylose–rhamnose supplemented deoxycholate hydrogen sulphide agar, enabled isolation of E. albertii when at least 1 CFU of the bacterium was present per gram of chicken meat. This level of enrichment was superior to those obtained using buffered peptone water, modified-EC broth, or mTSB (with novobiocin). Conclusions Novobiocin–cefixime–tellurite supplemented modified tryptic soy broth enabled effective enrichment of E. albertii from poultry samples and was helpful for isolation of this bacterium. Significance and Impact of Study To our knowledge, this is the first report of selective enrichment of E. albertii from poultry samples.
- Published
- 2022
48. Clinical efficiency and safety of Hsp90 inhibitor Novobiocin in avian tibial dyschondroplasia.
- Author
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Nabi, Fazul, Iqbal, Muhammad K., Zhang, Hui, Rehman, Mujeeb Ur, Shahzad, Muhammad, Huang, Shucheng, Han, Zhaoqing, Mehmood, Khalid, Ahmed, Nisar, Chachar, Bahram, Arain, Muhammad A., and Li, Jiakui
- Subjects
- *
TIBIAL dyschondroplasia in poultry , *HEAT shock proteins , *NOVOBIOCIN , *PROTEOGLYCANS , *IMMUNOHISTOCHEMISTRY - Abstract
Tibial dyschondroplasia (TD) is a bone defect of broilers and other poultry birds that disturbs growth plate and it causes lameness. Previously we evaluated differential expression of multiple genes involved in growth plate angiogenesis and reported the safety and efficacious of medicinal plant root extracted for controlling TD. In this study, clinical and protective effect of an antibiotic Novobiocin (Hsp90 inhibitor) and expression of Hsp90 and proteoglycan aggrecan was examined. The chicks were divided into three groups; Control, thiram‐induced TD, and Novobiocin injected TD. After the induction of TD, the Novobiocin was administered through intraperitoneal route to TD‐affected birds until the end of the experiment. The expressions and localization of Hsp90 were evaluated by qRT‐PCR, immunohistochemistry (IHC) and western blot, respectively. Morphological, histological examinations, and serum biomarker levels were evaluated to assess specificity and protective effects of Novobiocin. The results showed that TD causing retarded growth, enlarged growth plate, distended chondrocytes, irregular columns of cells, decreased antioxidant capacity, reduced protein levels of proteoglycan aggrecan, and upregulated in Hsp90 expression (p < 0.05) in dyschondroplastic birds as compared with control. Novobiocin treatment restored growth plate morphology, reducing width, stimulated chondrocyte differentiation, sprouting blood vessels, corrected oxidative imbalance, decreased Hsp90 expressions and increased aggrecan level. Novobiocin treatment controlled lameness and improved growth in broiler chicken induced by thiram. In conclusion, the accumulation of the cartilage and up‐regulated Hsp90 are associated with TD pathogenesis and irregular chondrocyte morphology in TD is along with reduced aggrecan levels in the growth plate. Our results indicate that Novobiocin treatment has potential to reduce TD by controlling the expression of Hsp90 in addition to improve growth and hepatic toxicity in broiler chicken. [ABSTRACT FROM AUTHOR]
- Published
- 2018
- Full Text
- View/download PDF
49. Anticancer activity of methylene blue via inhibition of heat shock protein 70.
- Author
-
Sanchala, Dhaval, Bhatt, Lokesh Kumar, Pethe, Prasad, Shelat, Ruchita, and Kulkarni, Yogesh A.
- Subjects
- *
HEAT shock proteins , *LUNG cancer , *METHYLENE blue , *NOVOBIOCIN , *OXIDATIVE stress , *BIOLOGICAL tags - Abstract
Graphical abstract Abstract Introduction Heat shock protein 70 (Hsp70) and heat shock protein 90 (Hsp90) chaperones are indispensable to lung cancer cells for their survival and proliferation. In this study we evaluated and compared anticancer potential of methylene blue (MB) as an Hsp70 inhibitor, novobiocin (NB) a well-known Hsp90 inhibitor and their combination. Methods In vitro evaluation was done by cell viability assays, fluorescent staining, and flow cytometry analysis using A549 non-small cell lung cancer cells. In vivo anticancer activity was investigated by evaluating oxidative stress, tumor biomarkers, weight, lung microarchitecture, and Hsp70 and Hsp90 inhibitions via immunoblotting in benzo[a]pyrene induced lung carcinogenesis mice model. Results Using A549 NSCLC cells, we found MB demonstrated lower cell viability versus NB. Together, MB + NB resulted in further decrease in cell viability. SRB assay revealed significantly superior and similar potency for MB versus NB and MB + NB (1:1) versus MB, respectively. Fluorescent staining and flow cytometry analysis displayed early apoptosis by MB (11.4%); early and late apoptosis by MB + NB (13.8%). In vivo , MB significantly inhibited Hsp70. Furthermore, MB significantly alleviated tumor biomarkers (ADA and LDH) and improved lung histopathological features more than NB. Additionally, MB significantly improved SOD, not more than MB + NB or NB and improved LPO. Conclusion MB demonstrated potent anticancer activity in vitro and in vivo via inhibition of Hsp70 in benzo[a]pyrene induced lung carcinogenesis in mice. [ABSTRACT FROM AUTHOR]
- Published
- 2018
- Full Text
- View/download PDF
50. Novobiocin, a Newly Found TRPV1 Inhibitor, Attenuates the Expression of TRPV1 in Rat Intestine and Intestinal Epithelial Cell Line IEC-6.
- Author
-
Liang, Qianying, Lv, Xueli, Cai, Qing, Cai, Yun, Zhao, Boxin, and Li, Guofeng
- Abstract
Background and Purpose: Novobiocin (NOVO), an ABC transporter inhibitor, decreases intestinal wall permeability of capsaicin (CAP), an ABC transporter substrate. However, the mechanism of this effect is not consistent with the action of NOVO as an ABC transporter inhibitor. We previously found that CAP can also be transported via TRPV1, which was site-specific in the permeability of CAP across the intestine. We explored the regulation by NOVO of TRPV1 in the present study. Methods: Rats and transfected IEC-6 cells were used as the models to assess intestinal permeability and expression of TRPV1. Ussing chamber and intracellular accumulation were used to evaluate the influence of NOVO on the transport of CAP in vitro. The expression of TRPV1 was detected after administration of NOVO by qRT-PCR, western blot and immunofluorescent imaging. In addition, MTT and lactate dehydrogenase (LDH) were used to evaluate the cytotoxicity of NOVO in both rat and cell models. Finally, the effect of NOVO on the absorption of CAP in vivo was studied by LC-MS/MS. Results: In vitro data showed that there existed a dose-dependent relationship in the range of concentration between 5 and 50 μM, and even 5 μM NOVO could decrease intestinal permeability of CAP across the intestine. Meanwhile, cytosolic accumulation of CAP decreased when NOVO was used simultaneously or 24 h in advance. NOVO exhibited an inhibition level similar to that of ruthenium red (RR) or SB-705498, a TRPV1-specific inhibitor. NOVO down-regulated TRPV1 expression in the intestine and in transfected cells in a concentration-dependent fashion, hinting that its inhibition of the permeability of CAP is due to its inhibition of TRPV1 expression. Immunofluorescent imaging data showed that the fluorescence intensity of TRPV1 was reduced after pre-treatment with NOVO and SB-705498. In vivo data further demonstrated that oral co-administration of NOVO decreased C
max and AUC of CAP in dosage-dependent ways, consistent with its role as a TRPV1 inhibitor. Conclusion: NOVO could be a potential TRPV1 inhibitor by attenuating the expression of TRPV1 and may be used to attenuate permeability of TRPV1 substrates. [ABSTRACT FROM AUTHOR]- Published
- 2018
- Full Text
- View/download PDF
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