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[Display omitted] • Design and synthesis of quaternization or dimerization norharmane analogues are described. • Their anti-MRSA activities are evaluated, and SARs are summarized. • Compound 5a exhibits potent bactericidal activity in vitro and in vivo with low toxicity. • Compound 5a could disrupt bacterial biofilm and damage the membrane. • Metabolomics analysis is used to systematically investigate the mechanisms. Methicillin-resistant Staphylococcus aureus (MRSA)-caused infections greatly threaten public health. The discovery of natural-product-based anti-MRSA agents for treating infectious diseases has become one of the current research focuses. This study aims to identify promising anti-MRSA agents with a clear mechanism based on natural norharmane modified by quaternization or dimerization. A total of 32 norharmane analogues were prepared and characterized. Their antibacterial activities and resistance development propensity were tested by the broth double-dilution method. Cell counting kit-8 and hemolysis experiments were used to assess their biosafety. The plasma stability, bactericidal mode, and biofilm disruption effects were examined by colony counting and crystal violet staining assays. Fluorescence microscopy, metabolomic analysis, docking simulation and spectra titration revealed its anti-MRSA mechanisms. The mouse skin infection model was used to investigate the in vivo efficacy. Compound 5a was selected as a potential anti-MRSA agent, which exhibited potent anti-MRSA activity in vitro and in vivo , low cytotoxicity and hemolysis under an effective dose. Moreover, compound 5a showed good stability in 50% plasma, a low tendency of resistance development and capabilities to disrupt bacterial biofilms. The mechanism studies revealed that compound 5a could inhibit the biosynthesis of bacteria cell walls, damage the membrane, disturb energy metabolism and amino acid metabolism pathways, and interfere with protein synthesis and nucleic acid function. These results suggested that compound 5a is a promising candidate for combating MRSA infections, providing valuable information for further exploiting a new generation of therapeutic antibiotics. [ABSTRACT FROM AUTHOR]

Introduction: Methicillin-resistant Staphylococcus aureus (MRSA)-caused infections greatly threaten public health. The discovery of natural-product-based anti-MRSA agents for treating infectious diseases has become one of the current research focuses. Objectives: This study aims to identify promising anti-MRSA agents with a clear mechanism based on natural norharmane modified by quaternization or dimerization. Methods: A total of 32 norharmane analogues were prepared and characterized. Their antibacterial activities and resistance development propensity were tested by the broth double-dilution method. Cell counting kit-8 and hemolysis experiments were used to assess their biosafety. The plasma stability, bactericidal mode, and biofilm disruption effects were examined by colony counting and crystal violet staining assays. Fluorescence microscopy, metabolomic analysis, docking simulation and spectra titration revealed its anti-MRSA mechanisms. The mouse skin infection model was used to investigate the in vivo efficacy. Results: Compound 5a was selected as a potential anti-MRSA agent, which exhibited potent anti-MRSA activity in vitro and in vivo, low cytotoxicity and hemolysis under an effective dose. Moreover, compound 5a showed good stability in 50% plasma, a low tendency of resistance development and capabilities to disrupt bacterial biofilms. The mechanism studies revealed that compound 5a could inhibit the biosynthesis of bacteria cell walls, damage the membrane, disturb energy metabolism and amino acid metabolism pathways, and interfere with protein synthesis and nucleic acid function. Conclusions: These results suggested that compound 5a is a promising candidate for combating MRSA infections, providing valuable information for further exploiting a new generation of therapeutic antibiotics.

The emergence of drug-resistant bacteria, particularly methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE), has increased the need to discover novel antimicrobial agents that are effective against these species. Here, we describe the identification and purification of the mutacin BHT-B-like gene locus and bacteriocin peptide from Streptococcus ursoris, which is closely related to Streptococcus ratti; hence, we named this bacteriocin ursoricin. Ursoricin is a cationic, chromosome-encoded peptide that has potent antimicrobial effects against Gram-positive pathogens, including MRSA and VRE, with minimum inhibitory concentrations in the micromolar range. Ursoricin also inhibits the biofilm formation of high biofilm-form ing S. aureus. Antibacterial activity was retained after treatment at 100°C for 60 min at a pH range of 3-9 and was partially reduced by treatment with proteinase K for 2 h (63% residual activity). The potent anti-MRSA, anti-VRE, and antibiofilm effects of ursoricin suggest that it is a possible candidate for the treatment of MRSA, VRE, and biofilm-associated infections. [ABSTRACT FROM AUTHOR]

A new pyrone derivative 11-hydroxypyrophen (1), together with pyrophen (2) and six naphtho-γ-pyrones (3–8), were obtained from the culture extract of Aspergillus niger Pas67. All isolated compounds were evaluated for their antibacterial activities against methicillin-resistant Staphylococcus aureus (MRSA). Compounds 4 and 8 showed significant antibacterial activity against MRSA with minimum inhibitory concentration values (MICs) of 25 and 16 μg/mL, while compounds 1 and 2 did not display anti-MRSA activity. [ABSTRACT FROM AUTHOR]

A rapid method has been developed for the synthesis of 3‐arylphthalides from readily available starting materials. We describe herein a direct approach based on a simple Friedel‐Crafts condensation between an aromatic ester and an aldehyde promoted by a mixture of phosphorus pentoxide and methanesulfonic acid (Eaton's reagent) under metal and solvent‐free conditions. Due to their similarity to cytosporone E (a natural antibacterial phthalide), some of the synthesized compounds were tested as antibacterial agents against methicillin‐resistant strain of Staphylococcus aureus. [ABSTRACT FROM AUTHOR]

Propolis is a naturally occurring substance with beneficial properties; bees produce it from various plant sources, and it is an anti-inflammatory and therapeutic resinous substance. This study aimed to enhance the biological features of propolis extract by loading it onto active film. Firstly, extraction was performed using three solvent systems, and their total phenolic, flavonoid, and antioxidant activity was measured. Propolis ethanol extract (EEP) was evaluated for phenolic fraction content and then chosen to prepare a chitosan-loaded emulsion with several concentrations. The antibacterial, anti-mycotic, and anti-mycotoxigenic properties of the extract and nanoemulsion were assessed. PPE's cytotoxicity and nanoemulsion were evaluated using brine shrimp and cell line assays. Results indicate higher phenolic (322.57 ± 4.28 mg GAE/g DW), flavonoid (257.64 ± 5.27 mg QE/g DW), and antioxidant activity of the EEP. The phenolic fraction is distinguished by 18 phenolic acids with high p-hydroxybenzoic content (171.75 ± 1.64 µg/g) and 12 flavonoid compounds with high pinocembrin and quercetin content (695.91 ± 1.76 and 532.35 ± 1.88 µg/g, respectively). Phenolic acid derivatives (3,4-Dihydroxybenzaldehyde, 3,4-Dihydroxyphenol acetate, and di-methoxy cinnamic) are also found. Concentrations of 50, 100, 150, and 200 ng EEP loaded on chitosan nanoemulsion reflect significant antibacterial activity against pathogenic bacteria, particularly methicillin-resistant Staphylococcus aureus (MRSA) and toxigenic fungi, particularly Fusarium. Among the four EEP-loaded concentrations, the nanoemulsion with 150 ng showed outstanding features. Using a simulated medium, 150 and 200 ng of EEP-loaded chitosan nanoemulsion concentrations can stop zearalenone production in Fusarium media with complete fungi inhibition. Also, it reduced aflatoxins production in Aspergillus media, with fungal inhibition (up to 47.18%). These results recommended the EEP-chitosan application for pharmaceutics and medical use as a comprehensive wound healing agent. [ABSTRACT FROM AUTHOR]

Introduction: Exploring endophytic fungi isolated from medicinal herbs could be a turning point in the research of secondary metabolites biosynthesis, as these endophytic fungi are capable of synthesizing the similar compounds as their host plant. The advantages of manipulating endophytic fungi for bioactive compound production are the reduction of dependency rate on slow-growing and rare plants, cost-effective, continuous process, environmentally friendly and high yield in a short period. Thus, the current study envisages investigating the influence of culture conditions against the anti-MRSA potential production of the endophytic fungal isolate, Ceratobasidium ramicola IBRLCM127 isolated from the local medicinal plant Curcuma mangga Valeton & Zijp. Methods: The endophytic fungal isolate was used to produce fungal metabolites through submerged fermentation. The physical parameter improvement was investigated using the 'one-factor-at-atime' technique. The fungal fermentative broth was subjected to an anti-MRSA assay using Lorian method, whereas the growth of a fungus was determined based on the cell growth weight. Results: The highest anti-MRSA potential of 42.50±0.1 U/ml and 5.49±0.1 g/L of mycelial growth was observed after improving the basal medium containing yeast extract sucrose broth incorporated with water extract from the host plant, 6 days old of inoculum age, 2 agar plugs of mycelia, incubation temperature of 25 0C and 12 days of cultivation 12 days of cultivation shaken at 120 rpm in the absence of light. Conclusion: The improved culture conditions shorten the incubation period and yield a significant enhancement of anti-MRSA potential and fungal growth with 13.27% and 10.91%, respectively. [ABSTRACT FROM AUTHOR]

Streptomyces lunaelactis strains have been isolated from moonmilk deposits, which are calcium carbonate speleothems used for centuries in traditional medicine for their antimicrobial properties. Genome mining revealed that these strains are a remarkable example of a Streptomyces species with huge heterogeneity regarding their content in biosynthetic gene clusters (BGCs) for specialized metabolite production. BGC 28a is one of the cryptic BGCs that is only carried by a subgroup of S. lunaelactis strains for which in silico analysis predicted the production of nonribosomal peptide antibiotics containing the non-proteogenic amino acid piperazic acid (Piz). Comparative metabolomics of culture extracts of S. lunaelactis strains either holding or not holding BGC 28a combined with MS/MS-guided peptidogenomics and 1H/13C NMR allowed us to identify the cyclic hexapeptide with the amino acid sequence (D-Phe)-(L-HO-Ile)-(D-Piz)-(L-Piz)-(D-Piz)-(L-Piz), called lunaemycin A, as the main compound synthesized by BGC 28a. Molecular networking further identified 18 additional lunaemycins, with 14 of them having their structure elucidated by HRMS/MS. Antimicrobial assays demonstrated a significant bactericidal activity of lunaemycins against Gram-positive bacteria, including multi-drug resistant clinical isolates. Our work demonstrates how an accurate in silico analysis of a cryptic BGC can highly facilitate the identification, the structural elucidation, and the bioactivity of its associated specialized metabolites. [ABSTRACT FROM AUTHOR]

Two new isochromenes, 5-methoxy-3-methyl-7-prenyl-1H-isochromene (1) and 7-(3-hydroxypropyl)-5-methoxy-3-methyl-1H-isochromene (2), along with four known ones (3–6) were isolated from the fermentation products of the Nicotiana tabacum-derived endophytic fungus Aspergillus versicolor. Their structures were elucidated by spectroscopic methods, including extensive 1D and 2D NMR techniques. Compounds 1 and 2 were evaluated for their anti-tobacco mosaic virus (anti-TMV) and anti-methicillin-resistant Staphylococcus aureus (anti-MRSA) activities. The results showed that compounds 1 and 2 exhibited potential anti-TMV activities with inhibition rates of 36.5 and 42.2%, respectively, and also showed good anti-MRSA activities with IZD of 16.8 ± 2.2 and 20.6 ± 2.5 mm, respectively. [ABSTRACT FROM AUTHOR]

The rapid emergence of antibiotic resistance and the scarcity of novel antibacterial agents have necessitated an urgent pursuit for the discovery and development of novel antibacterial agents against multidrug-resistant bacteria. This study involved the design and synthesis of series of novel indole-benzosulfonamide oleanolic acid (OA) derivatives, in which the indole and benzosulfonamide pharmacophores were introduced into the OA skeleton semisynthetically. These target OA derivatives show antibacterial activity against Staphylococcus strains in vitro and in vivo. Among them, derivative c17 was the most promising antibacterial agent while compared with the positive control of norfloxacin, especially against methicillin-resistant Staphylococcus aureus (MRSA) in vitro. In addition, derivative c17 also showed remarkable efficacy against MRSA-infected murine skin model, leading to a significant reduction of bacterial counts during this in vivo study. Furthermore, some preliminary studies indicated that derivative c17 could effectively inhibit and eradicate the biofilm formation, disrupt the integrity of the bacterial cell membrane. Moreover, derivative c17 showed low hemolytic activity and low toxicity to mammalian cells of NIH 3T3 and HEK 293T. These aforementioned findings strongly support the potential of novel indole-benzosulfonamide OA derivatives as anti-MRSA agents. [Display omitted] • Novel indole-benzosulfonamide oleanolic acid derivatives were constructed. • Derivative c17 showed more potential than norfloxacin against MRSA. • Derivative c17 could disrupt cell membrane and restrain metabolism. • Derivative c17 showed antibacterial efficacy in MRSA-infected skin murine model. [ABSTRACT FROM AUTHOR]

Propolis is a naturally occurring substance with beneficial properties; bees produce it from various plant sources, and it is an anti-inflammatory and therapeutic resinous substance. This study aimed to enhance the biological features of propolis extract by loading it onto active film. Firstly, extraction was performed using three solvent systems, and their total phenolic, flavonoid, and antioxidant activity was measured. Propolis ethanol extract (EEP) was evaluated for phenolic fraction content and then chosen to prepare a chitosan-loaded emulsion with several concentrations. The antibacterial, anti-mycotic, and anti-mycotoxigenic properties of the extract and nanoemulsion were assessed. PPE’s cytotoxicity and nanoemulsion were evaluated using brine shrimp and cell line assays. Results indicate higher phenolic (322.57 ± 4.28 mg GAE/g DW), flavonoid (257.64 ± 5.27 mg QE/g DW), and antioxidant activity of the EEP. The phenolic fraction is distinguished by 18 phenolic acids with high p-hydroxybenzoic content (171.75 ± 1.64 µg/g) and 12 flavonoid compounds with high pinocembrin and quercetin content (695.91 ± 1.76 and 532.35 ± 1.88 µg/g, respectively). Phenolic acid derivatives (3,4-Dihydroxybenzaldehyde, 3,4-Dihydroxyphenol acetate, and di-methoxy cinnamic) are also found. Concentrations of 50, 100, 150, and 200 ng EEP loaded on chitosan nanoemulsion reflect significant antibacterial activity against pathogenic bacteria, particularly methicillin-resistant Staphylococcus aureus (MRSA) and toxigenic fungi, particularly Fusarium. Among the four EEP-loaded concentrations, the nanoemulsion with 150 ng showed outstanding features. Using a simulated medium, 150 and 200 ng of EEP-loaded chitosan nanoemulsion concentrations can stop zearalenone production in Fusarium media with complete fungi inhibition. Also, it reduced aflatoxins production in Aspergillus media, with fungal inhibition (up to 47.18%). These results recommended the EEP-chitosan application for pharmaceutics and medical use as a comprehensive wound healing agent.

Increased use of antibiotics globally has led to the threat of antibiotic resistance; this drove the urge of researchers toward discovering more potent and broad-spectrum antibiotics. Levonadifloxacin (LND) is the very first antibiotic developed by an Indian company Wockhardt. It is S (–) isomer of another broad-spectrum antibiotic Nadifloxacin which is used topically for skin, soft tissue bacterial infection. LND belongs to the benzo quinolizine category which is a subclass of fluoroquinolone, indicated for ABSSIS, CABP, and other infections including diabetic foot infection; formulated as l-arginine salt of levonadifloxacin (WCK177) for IV and l-alanine ester mesylate salt as alalevonadifloxacin (WCK2349) for oral administration. It generally shows dominant antibacterial activity against Gram-negative, and positive bacterial infections, particularly toward methicillin-resistant Staphylococcus aureus (MRSA) by dual inhibition of DNA gyrase and topoisomerase IV. Producing quality product that complies to regulatory requirements is a big concern for pharma industries. To this context, validated analytical methods for routine quality control are essential for quantification of LND as an API alone and together with pharmaceutical formulations. This review suggests therapeutic, pharmacological, and analytical aspects regarding the novel drug LND and particularly focuses on discussing various reported analytical methods present for analytical or bioanalytical estimation of the drug and suggest to develop a simple and validated method which also complies to green chemistry. [ABSTRACT FROM AUTHOR]

Methicillin-resistant Staphylococcus aureus (MRSA) is a disreputable pathogenic bacterium that has been proven to colonize the intestinal tract. The goal of this study is to find anti-MRSA probiotic yeast from food and evaluate its probiotic characteristics and safety. Finally, 15 strains were isolated from fruit peel with anti-MRSA ability. Using DNA sequence analysis, they were identified as the genus Hanseniaspora (7 strains) and Starmerella (8 strains). Starmerella bacillaris CC-PT4 (CGMCC No. 23573) that was isolated from the grape peel has good auto-aggregation ability and hydrophobicity, and can tolerate 0.3% bile, pH 2, simulated gastric fluid (SGF), and simulated intestinal fluid (SIF). Strikingly, Starmerella bacillaris CC-PT4, like commercial probiotic Saccharomyces boulardii CNCM I-745 (Florastor ®), can adapt to the temperature of the human body (37 ℃). After safety assessment, this strain is sensitive to amphotericin B and cannot produced β-hemolytic activities. Overall, this study provides a new candidate for probiotic yeast with anti-MRSA ability. [ABSTRACT FROM AUTHOR]

Ethnopharmacological Relevance: Caryopteris trichosphaera W. W. Sm., a traditional ethnic medicine, was recorded in the Compendium of Materia Medica for treating wound infection by pathogenic infection. However, its antibacterial potential and bioactive compositions against drug-resistant bacteria need to be validated., Aim of the Study: To investigate the chemical constituents of C. trichosphaera and explore its anti-MRSA component in vitro and in vivo, together with the antibacterial mechanism., Materials and Methods: Bioactive constituents investigation was carried out by phytochemical method and antibacterial screening. The antibacterial mechanism was predicted by network pharmacology, which was further validated by time-kill analysis, membrane function tests, multigenerational resistance induction assay and biofilm test, and metabolomics analysis in vitro. In addition, MRSA-induced epidermal infection in mice was selected to evaluate its pharmacological effect in vivo., Results: Six antibacterial diterpenoids against MRSA and VRE with MIC values 4-32 μg/mL from C. trichosphaera were reported for the first time, in which the major compound cativic acid (1) disrupted MRSA cell membranes by modulating permeability, depolarization, and fluidity while increasing reactive oxygen species (ROS) and malondialdehyde (MDA) levels. It also displayed remarkable anti-biofilm activity without inducing bacterial resistance or cytotoxicity. Moreover, cativic acid affected MRSA biosynthesis of cofactors, amino acid biosynthesis, nucleotide metabolism by metabolomics analysis. Furthermore, cativic acid accelerated wound healing in MRSA-infected mouse skin wounds, even better than vancomycin., Conclusions: The results supported the traditional use of C. trichosphaera, and presented unreported anti-MRSA agent, cativic acid, as a plant-derived bactericide in vitro and in vivo for the first time., 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 Elsevier B.V. All rights reserved.)

Monoterpene derivatives are of great biological relevance in the pharmaceutical industry. In the present study, pyrrolidine derivative of a carvotacetone, 3-O-benzylcarvotacetone (1), and selected monoterpenes (3-hydroxy-2-isopropyl-5-methyl-p-benzoquinone (3) and cis-piperitol (5)) were prepared to provide (R)-1-(4-(benzyloxy)-5-isopropyl-2-methylcyclohexa-1,3-dien-1-yl)-pyrrolidine (2), 2-isopropyl-5-methyl-3,6-dioxocyclohexa-1,4-dien-1-yl acetate (4), cis-3-hydroxypiperitone (6) and carvacrol (7). Structure of 2 was determined based on NMR and HRMS spectral data. Compound 4 exhibited activity against fungi Cryptococcus neoformans with an IC50 value of < 0.8 µg/mL. In addition, this compound 4 had an IC50 value of 14.97 µg/mL against methicillin resistant Staphylococcus aureus bacteria. Previous to the current study, both compound 6 and 7 had been reported to have anti-microbial and anti-fungal activities. [ABSTRACT FROM AUTHOR]

[Display omitted] • 28 N -acylpiperidines were prepared using a three-step and versatile protocol. • Compounds showed antibacterial activity against MRSA and multiresistant K. pneumoniae. • The most active piperidines against K. pneumoniae bore a chlorine atom at the arylamino moiety. • Molecular docking offered insights into the binding mode of the series into the FabI catalytic domain. • The series become an attractive scaffold for the design of more potent antimicrobials. We report a concise synthesis of N -acylated piperidines through a Knoevenagel-Doebner condensation/amide construction/ amination sequence. The design of the piperidines considered the pharmacophoric features found in previously reported inhibitors of FabI, an enzyme implicated in bacterial fatty acid biosynthesis. After the microbiological evaluation at 50 μM, the analogs displayed moderate activity against some pathogens from the ESKAPE group, reaching up to 42 % of growth inhibition for MRSA , 54 % for K. pneumonia e, and 37 % for P. aeruginosa (multiresistant strains). Docking studies demonstrate that almost all of them docked satisfactorily into the catalytic domain of S. aureus FabI, maintaining a similar pose as other reported inhibitors. The results shown herein propose the N -acyl-4-arylaminopiperidines as the basis for the development of more active candidates. [ABSTRACT FROM AUTHOR]

Four new germacrane sesquiterpene dilactones, 2β-hydroxyl-11β,13-dihydrodeoxymikanolide (1), 3β-hydroxyl-11β,13-dihydrodeoxymikanolide (2), 1α,3β-dihydroxy-4,9-germacradiene-12,8:15,6-diolide (3), and (11β,13-dihydrodeoxymikanolide-13-yl)-adenine (4), together with five known ones (5–9) were isolated from the aerial parts of Mikania micrantha. Their structures were elucidated on the basis of extensive spectroscopic analysis. Compound 4 is featured with an adenine moiety in the molecule, which is the first nitrogen-containing sesquiterpenoid so far isolated from this plant species. These compounds were evaluated for their in vitro antibacterial activity against four Gram-(+) bacteria of Staphyloccocus aureus (SA), methicillin-resistant Staphylococcus aureus (MRSA), Bacillus cereus (BC) and Curtobacterium. flaccumfaciens (CF), and three Gram-(–) bacteria of Escherichia coli (EC), Salmonella. typhimurium (SA), and Pseudomonas Solanacearum (PS). Compounds 4 and 7–9 were found to show strong in vitro antibacterial activity toward all the tested bacteria with the MIC values ranging from 1.56 to 12.5 µg/mL. Notably, compounds 4 and 9 showed significant antibacterial activity against the drug-resistant bacterium of MRSA with MIC value 6.25 µg/mL, which was close to reference compound vancomycin (MIC 3.125 µg/mL). Compounds 4 and 7–9 were further revealed to show in vitro cytotoxic activity toward human tumor A549, HepG2, MCF-7, and HeLa cell lines, with IC50 values ranging from 8.97 to 27.39 μM. No antibacterial and cytotoxic activity were displayed for the other compounds. The present research provided new data to support that M. micrantha is rich in structurally diverse bioactive compounds worthy of further development for pharmaceutical applications and for crop protection in agricultural fields.

Chaetomium fungi produce a diversity of bioactive compounds. Chaetomium cochliodes SD-280 possesses 91 secondary metabolite gene clusters and exhibits strong antibacterial activity. One of the active compounds responsible for that activity, chetomin, has a minimum inhibitory concentration (MIC) for anti-methicillin-resistant Staphylococcus aureus (MRSA) of 0.05 μg/mL (vancomycin: 0.625 μg/mL). This study demonstrated that the addition of glutathione (GSH) can enhance chetomin yield dramatically, increasing its production 15.43-fold. Following genome sequencing, cluster prediction, and transcriptome and proteome analyses of the fungus were carried out. Furthermore, a relatively complete chetomin biosynthetic gene cluster was proposed, and the coding sequences were acquired. In the cluster of GSH-treated cells, proteome analysis revealed two up-regulated proteins that are critical enzymes for chetomin biosynthesis. One of these enzymes, a nonribosomal peptide synthetase (NRPS), was heterologously expressed in Aspergillus nidulans, and one of its metabolites was determined to be an intermediate in the chetomin biosynthetic pathway. We present here, to our knowledge, the first experimental evidence that chetomin exhibits strong bioactivity against MRSA. Our work also provides extensive insights into the biosynthetic pathway of chetomin, in particular identifying two key enzymes (glutathione S-transferase (CheG) and NRPS (CheP)) that substantially up-regulate chetomin. These mechanistic insights into chetomin biosynthesis will provide the foundation for further investigation into the anti-pathogenic properties and applications of chetomin. Key points: • Chetomin exhibits strong anti-MRSA activity with MIC of 0.05 μg/mL. • Addition of glutathione improved the yield of chetomin by 15.43-fold. • CheG and CheP involved in the chetomin biosynthesis were revealed for the first time. [ABSTRACT FROM AUTHOR]

Antibiotic resistance is widespread in clinical settings, indicating a serious problem with infectious disease treatment. Novel strategies such as using natural products derived from microbes are being explored, generating increased research interest to address this issue. Here, the antimicrobial property of gut-associated Bacillus species against multidrugresistant (MDR) strains; methicillin-resistant Staphylococcus aureus (MRSA), Escherichia coli producing extended-spectrum beta-lactamase (EsßL E. coli), and Pseudomonas aeruginosa producing metallo beta-lactamase (MßL P.aeruginosa) was evaluated using a cross-streak method and agar diffusion assay. The Bacillus isolates inhibited MRSA and ESßL E. coli with an average zone of inhibition of 9.57 ± 33.40 mm and 5.07 ± 32.69 mm, respectively, in the cross-streak method. The cell-free supernatant (CFS) of ten Bacillus species demonstrated anti-MRSA activity but was ineffective against ESßL E. coli and MßL P. aeruginosa. The relative enzyme activities of ten Bacillus isolates were determined in vitro, and amylase, caseinase, cellulase, lipase, and gelatinase production were confirmed. Isolates were identified as Bacillus siamensis, Bacillus velezensis, and Bacillus subtilis through biochemical tests and 16s rRNA sequence analysis. Minimum inhibitory concentrations (MICs) of the CFSs against MRSA range is between 12.5 and 25%. Bacillus species isolated from fish and snail guts exhibited antibacterial activity against MRSA. Therefore, it is imperative to confirm the presence of anti-MRSA active compounds in Bacillus CFS and characterize them further to determine their suitability for antimicrobial drug development. [ABSTRACT FROM AUTHOR]

Infectious diseases caused by multidrug-resistant bacteria such as methicillin-resistant Staphylococcus aureus, pose a significant threat to humanity. Persistent and repeated invasive infection with MRSA led to higher morbidity and mortality, and required comprehensive measures in treatment and prevention. Zanthoxylum nitidum (Roxb.) DC. is used as detoxifying, analgesic, and hemostatic herbal medicine for thousands of years. Previously pharmacological studies showed that Z. nitidum had antibacterial bioactivity, but only the MIC of a few compounds, crude extracts, and fractions were reported. In our ongoing endeavor to explore bioactive compounds, two new coumarins, 6-(3-oxo-butyl)-limettin (1) and toddalin I (2), and 24 known compounds were isolated from the roots of Z. nitidum, in which two isoquinoline alkaloids, 6-acetonyl-dihydrofagaridine (16) and 6-acetonyl-dihydrochelerythrine (17) showed anti-MRSA bioactivity in vitro and in vivo. Both 16 and 17 showed synergistic action with ampicillin, which decreased the MIC significantly, and both compounds had a significant ability to destroy bacterial biofilm combined with ampicillin. The combined administration showed a strong scavenging effect on the planktonic bacteria in vitro and cleared skin infection effectively in the model of wound infection in vivo. Furthermore, compound 16 inhibited the efflux of the drug by combining with ampicillin or EtBr, resulting in the MIC decreased obviously. Our investigation supported the traditional use of Z. nitidum in treating infections caused by bacteria, and might provide new natural products to reduce the use of antibiotics and the treatment of drug-resistance bacteria.

ABSTRACT Human neutrophil peptide-1 (HNP-1) is a promising antibiotic candidate, but its clinical applications have been hampered by challenges during mass production and an inadequate understanding of its bactericidal mechanisms. In this study, we demonstrated that Escherichia coli expressing full-length preproHNP-1 secretes a soluble form of HNP-1, which can be recovered from the total cell lysate after isopropyl thio-β-d-galactoside (IPTG) induction and ultrafiltration. Label-free quantitative proteomics and co-immunoprecipitation experiments revealed that HNP-1 induces cell apoptosis in bacteria by causing DNA and membrane damage. Notably, we found that HNP-1 disrupts the DNA damage response pathway by interfering with the binding of RecA to single-stranded DNA (ssDNA). Further experiments demonstrated that HNP-1 encapsulated in liposomes inhibits the growth of methicillin-resistant Staphylococcus aureus (MRSA) and meropenem-resistant Pseudomonas aeruginosa (MRPA). These results indicated that recombinant protein expression may be a simple and cost-effective solution to produce HNP-1 and that RecA inhibition via HNP-1 may serve as an alternative strategy to counteract antibiotic resistance. IMPORTANCE Human neutrophil peptide-1 (HNP-1) is a promising antibiotic candidate, but its clinical application has been hampered by the difficulty of mass production and an inadequate understanding of its bactericidal mechanisms. In this study, we demonstrated that recombinant protein expression combined with ultrafiltration may be a simple and cost-effective solution to HNP-1 production. We further found that HNP-1 induces bacterial apoptosis and prevents its SOS repair pathway from binding to the RecA protein, which may be a new antibacterial mechanism. In addition, we showed that HNP-1 encapsulated in liposomes inhibits the growth of methicillin-resistant Staphylococcus aureus (MRSA) and meropenem-resistant Pseudomonas aeruginosa (MRPA). These results provide new insights into the production and antibacterial mechanism of HNP-1, both of which may promote its clinical application.

Streptomyces lunaelactis strains have been isolated from moonmilk deposits, which are calcium carbonate speleothems used for centuries in traditional medicine for their antimicrobial properties. Genome mining revealed that these strains are a remarkable example of a Streptomyces species with huge heterogeneity regarding their content in biosynthetic gene clusters (BGCs) for specialized metabolite production. BGC 28a is one of the cryptic BGCs that is only carried by a subgroup of S. lunaelactis strains for which in silico analysis predicted the production of nonribosomal peptide antibiotics containing the non-proteogenic amino acid piperazic acid (Piz). Comparative metabolomics of culture extracts of S. lunaelactis strains either holding or not holding BGC 28a combined with MS/MS-guided peptidogenomics and 1H/13C NMR allowed us to identify the cyclic hexapeptide with the amino acid sequence (D-Phe)-(L-HO-Ile)-(D-Piz)-(L-Piz)-(D-Piz)-(L-Piz), called lunaemycin A, as the main compound synthesized by BGC 28a. Molecular networking further identified 18 additional lunaemycins, with 14 of them having their structure elucidated by HRMS/MS. Antimicrobial assays demonstrated a significant bactericidal activity of lunaemycins against Gram-positive bacteria, including multi-drug resistant clinical isolates. Our work demonstrates how an accurate in silico analysis of a cryptic BGC can highly facilitate the identification, the structural elucidation, and the bioactivity of its associated specialized metabolites.

The emergence of drug-resistant bacteria, particularly methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE), has increased the need to discover novel antimicrobial agents that are effective against these species. Here, we describe the identification and purification of the mutacin BHT-B-like gene locus and bacteriocin peptide from Streptococcus ursoris , which is closely related to Streptococcus ratti ; hence, we named this bacteriocin ursoricin. Ursoricin is a cationic, chromosome-encoded peptide that has potent antimicrobial effects against Gram-positive pathogens, including MRSA and VRE, with minimum inhibitory concentrations in the micromolar range. Ursoricin also inhibits the biofilm formation of high biofilm-forming S. aureus . Antibacterial activity was retained after treatment at 100°C for 60 min at a pH range of 3-9 and was partially reduced by treatment with proteinase K for 2 h (63% residual activity). The potent anti-MRSA, anti-VRE, and antibiofilm effects of ursoricin suggest that it is a possible candidate for the treatment of MRSA, VRE, and biofilm-associated infections., Importance: The emergence of multidrug-resistant bacteria worldwide has posed a significant public health threat and economic burdens that make the identification and development of novel antimicrobial agents urgent. Bacteriocins are promising new agents that exhibit antibacterial activity against a wide range of human pathogens. In this study, we report that the bacteriocin produced by Streptococcus ursoris showed good antibacterial activity against a wide range of Staphylococcus aureus and enterococcus strains, particularly methicillin-resistant Staphylococcus aureus , vancomycin-resistant enterococci, and high biofilm-forming S. aureus . Interestingly, this bacteriocin had a stronger effect on S. aureus than on Staphylococcus epidermidis , which is a major commensal bacterium in human skin; this result is important when considering the disturbance of bacterial flora, especially on the skin, mediated by the application of antibacterial agents., Competing Interests: The authors declare no conflict of interest.

This study aimed to evaluate the antibacterial activities of 61 plant extracts from 49 Malaysian ethnomedicinal plants and to investigate the interaction of the active plant extracts in combination with synthetic antibiotics against the MSSA and MRSA strains. The minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of the plant extracts were determined using a microdilution method against MSSA and MRSA strains. The interaction between active plant extracts and the antibiotics was assessed using the checkerboard method. The total fractional inhibitory concentration (∑FIC) indices from the combination were calculated to determine the nature of the interaction. Out of the 61 plant extracts tested against the MSSA strain, 7 plant extracts (̴ 11%) showed MIC values of less than 200 μg/mL, 17 extracts (̴ 28%) showed MIC between 200 and 800 µg/mL and seed extracts of Areca catechu showed MBC values of 400 μg/mL. The seed extract of A. catechu showed MIC and MBC of 400 μg/mL against the MRSA strains while leaf extract of Cocos nucifera showed MIC of 400 μg/mL against MRSA NCTC 12493. When the active plant extracts (MIC ≤ 200 µg/mL for MSSA, and ≤ 400 µg/mL for MRSA) were tested in combination with vancomycin and ciprofloxacin, they showed no interaction against both MSSA and MRSA with ∑FIC between 1.06 and 2.03. These findings provide a preliminary overview of the anti-MSSA and anti-MRSA properties of Malaysian ethnobotanical plants to combat Staphylococcal infections. Further research is needed to establish an antibacterial profile of the tested plant extracts. [ABSTRACT FROM AUTHOR]

Ag-doped sol-gel derived bioactive glass-ceramic particles (Ag-BG) were used to fabricate highly porous scaffolds exhibiting advanced antibacterial properties and formation of an apatite-like layer. The applied heat treatment for the development of the 3D Ag-BG scaffolds was selected after the characterization of the thermal behavior of Ag-BG particles using differential thermal analysis (DTA), thermogravimetric analysis (TGA), and hot stage microscopy (HSM). The structural characteristics of the scaffolds were studied using optical microscopy, scanning electron microscopy (SEM), energy dispersive spectroscopy (EDS), micro-computerized tomography (Micro-CT), X-ray diffraction (XRD), Fourier-transformed infrared (FTIR), magic angle spinning nuclear magnetic resonance (MAS-NMR), and transmission electron microscopy (TEM) to correlate how the characteristics in the hierarchal structure of the Ag-BG scaffolds affected their antibacterial performance and apatite forming ability. Methicillin-resistant Staphylococcus aureus (MRSA) was used to evaluate the antibacterial response of the Ag-BG scaffolds. The observed characteristics make these Ag-BG scaffolds attractive candidates for biomedical applications. [ABSTRACT FROM AUTHOR]

Methicillin-resistant Staphylococcus aureus (MRSA) is a severe threat to public health globally. The development of novel agents has encountered the repeated mechanism of drug resistance. This study aimed to investigate an anti-MRSA substance isolated from a promising soil bacterium. The result showed that an isolate (WUL10) was in the Brevibacillus genus. The minimum inhibitory concentration (MIC) of the purified substance was 1 µg/mL against S. aureus TISTR 517 and MRSA strains. This substance showed the bactericidal effect at the concentration of 1–2 µg/mL against these bacterial indicators. The activity of the substance retained more than 95% when encountering high temperatures and a wide range of pH, but it was sensitive to proteolytic enzymes and SDS. It was identified as a novel antimicrobial peptide (KVLVKYLGGLLKLAALMV-COOH) with the predicted structure of α-helix. The substance could rupture the cell wall of the tested pathogen. MIC and MBC of the synthesized peptide were 16 and 64 µg/mL, respectively. The difference in the activity between the isolated and synthetic peptides might be from the synergistic effects of other AMPs in the purified substance. This novel AMP would provide an advantage for further development of anti-MRSA substances to manage the situation of antibiotic resistance.

Three new polycyclic phenol derivatives, 2-acetyl-4-hydroxy-6H-furo [2,3-g]chromen-6-one (1), 2-(1′,2′-dihydroxypropan-2′-yl)-4-hydroxy-6H-furo [2,3-g][1]benzopyran-6-one (2) and 3,8,10-trihydroxy-4,9-dimethoxy-6H-benzo[c]chromen-6-one (8), along with seven known ones (3–7, 9 and 10) were isolated for the first time from the leaves of Spermacoce latifolia. Their structures were determined by spectroscopic analysis and comparison with literature-reported data. These compounds were tested for their in vitro antibacterial activity against four Gram-(+) bacteria: Staphyloccocus aureus (SA), methicillin-resistant Staphylococcus aureus (MRSA), Bacillus cereus (BC), Bacillus subtilis (BS), and the Gram-(−) bacterium Escherichia coli. Compounds 1, 2, 5 and 8 showed antibacterial activity toward SA, BC and BS with MIC values ranging from 7.8 to 62.5 µg/mL, but they were inactive to MRSA. Compound 4 not only showed the best antibacterial activity against SA, BC and BS, but it further displayed significant antibacterial activity against MRSA (MIC 1.95 µg/mL) even stronger than vancomycin (MIC 3.9 µg/mL). No compounds showed inhibitory activity toward E. coli. Further bioassay indicated that compounds 1, 4, 5, 6, 8 and 9 showed in vitro α-glucosidase inhibitory activity, among which compound 9 displayed the best α-glucosidase inhibitory activity with IC50 value (0.026 mM) about 15-fold stronger than the reference compound acarbose (IC50 0.408 mM). These results suggested that compounds 4, 8 and 9 were potentially highly valuable compounds worthy of consideration to be further developed as an effective anti-MRSA agent or effective α-glucosidase inhibitors, respectively. In addition, the obtained data also supported that S. latifolia was rich in structurally diverse bioactive compounds worthy of further investigation, at least in searching for potential antibiotics and α-glucosidase inhibitors.

Reaction of 6-alkoxy-2-oxo-2H-chromen-4-carbaldehydes with N-(2,3,4,6-tetra-O-acetyl-β-d-glucopyranosyl)thiosemicarbazide yielded corresponding thiosemicarbazones having 2H-chromen-2-one ring. In vitro evaluations showed that these 2H-chromen-2-one compounds exhibited remarkable antibacterial and antifungal activities against some typical bacteria and fungi. Representative compounds with MIC values of 0.78 − 1.56 μg/mL were 6c, 6g (against S. aureus), 6a, 6f (against S. epidermidis) (Gram-positive bacterial strains), 6e, 6g (against E. coli), 6b, 6e (against K. pneumoniae), and 6d–f (against S. typhimurium) (Gram-negative bacterial strains). Almost all thiosemicarbazones 6a–g had no activity against Gram-positive bacterial strain B. subtilis at these MIC values. Some compounds had strong inhibitory activity against several bacteria, such as 6b (for K. pneumoniae and S. typhimurium), 6d, 6e (for E. coli, K. pneumoniae, and S. typhimurium), 6f (for S. aureus, E. coli, and S. typhimurium), and 6g (for B. subtilis, S. aureus, E. coli, and K. pneumoniae). Some compounds had remarkable inhibitory activity against three clinical MRSA isolates with MIC values of 0.78–6.25 μg/mL. Docking study showed that compound 6g is compatible with the active site of S. aureus DNA gyrase 2XCT, which suggested that the tested compounds inhibited the synthesis of this enzyme. [ABSTRACT FROM AUTHOR]

A series of novel potentially biologically active fused [5:7] oxazepanone γ-lactams were synthesized and described. A series of functional group transformations, namely amination, syn-hydrogenation and intramolecular annulation reactions were used to obtain the [5:7] oxazepanone γ-lactams in reasonable yields. In the diastereoselective fused-annulation for the formation of the secondary ring, steric constrain and cisgeometrical configuration of C-3 and C-4 substituents were observed as the predetermined factors. These ring annulations were purposely constructed to suit the physicochemical enhancement of the biological activity of the title compounds via SAR study of γ-lactams. [ABSTRACT FROM AUTHOR]

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The inclusion complexes of tenofovir disoproxil fumarate (TDF) with p-sulfonato-calix[4]arene (SCX4) and p-sulfanatothiacalix[4]arene (TSCX4) macrocycles are characterized through an array of experiments including 1H NMR, NOESY, HPLC, HRMS, FT-IR and PXRD in conjunction with the density functional theory. An encapsulation of TDF within SCX4 and TSCX4 macrocycles conduce 1:1 complexes those prevail over 1:2 or 1:3 Stoichiometries which exhibis distinct structural features. A loss of crystallinity accompanying the complexation ascertains the inclusion of the guest within the macrocycle. A comparison of the measured 13C NMR spectra of the complexes with individual hosts ascertains the cone conformation of SCX4 in such complexes as in its free state. It has been demonstrated that the TDF guest penetrates deeply within the cavity of SCX4 facilitating the hydrogen bonding interactions between adenine protons and the hydroxyl as well as methylene protons of the macrocycle. The measured 1H NMR spectra thus reveal large upfield signals (δ 8.35, 8.48 ppm) for adenine protons of the SCX4 complex. On the other hand, the partial encapsulation of TDF in TSCX4 reflects in the deshielding of hydroxyl protons in the measured 1H NMR spectra. The characteristic C=N and SO stretching vibrations in the infrared spectra engender'frequency shifts' in the opposite directions compared to the individual host or guest. A simple reverse phase high performance liquid chromatography method is presented. The adenine encapsulation further has been qualitatively correlated with MRSA activities. [ABSTRACT FROM AUTHOR]

The emergence of multi-drug-resistant microbial strains spurred the search for antimicrobial agents; as a result, two distinct approaches were combined: four in vitro studies and four corresponding molecular docking investigations. Antituberculosis, anti-methicillin-resistant Staphylococcus aureus (anti-MRSA), antifungal, and larvicidal activities of the crude extract, two fractions, and seven isolated compounds from Aspergillus terreus derived from Morus alba roots were explored. The isolated compounds (5 butyrolactones and 2 orsellinic acid derivatives) showed potent to moderate antitubercular activity with MIC values ranging from 1.95 to 62.5 μg/mL (compared to isoniazid, 0.24 μg/mL) and promising anti-MRSA potential with inhibition zone diameters ranging from 8 to 25 mm. Additionally, the in silico study proved that the isolated compounds bind to the two corresponding proteins' active sites with high to moderate -(C-Docker interaction energies) and stable interactions. The isolated compounds displayed antifungal activities against different fungal strains at diverse degrees of activity, among them compound (8"S,9")-dihydroxy-dihydrobutyrolactone I eliciting the best antifungal activity. Meanwhile, all isolated compounds, fractions, and the crude extract demonstrated extremely selective potent to moderate activity against Cryptococcus neoformans. The isolated five butyrolactone derivatives could develop potential mosquito larvicidal agents as a result of promising docking outcomes in the larval enzyme carboxylesterase., (© 2024 Wiley-VHCA AG, Zurich, Switzerland.)

Cycloaddition reactions such as intramolecular Diels–Alder (IMDA) are extremely important in constructing multicyclic scaffolds with diverse bioactivities. Using MycB as a biomarker, three new polyketides – Chaetolivacines A (1), B (3), and C (4) – with one known compound Myceliothermophin E (2) comprising of decalin and 4-hydroxy-2-pyridones were obtained from the culture of Chaetomium olivaceum SD-80A under the guidance of gene mining. The structures of these compounds were established using detailed 1D, 2D NMR, and high-resolution electron spray ionization mass spectroscopy (HRESIMS) analysis. The relative and absolute configurations of the compounds 1, 3, and 4 were elucidated by NOESY and ECD. The biosynthesis pathways of these compounds were proposed, which involves in three key genes ChaA [polyketide synthase-non-ribosomal peptide synthetases (PKS-NRPS)], ChaB, and ChaC. Compounds 1–4 were tested for their antimicrobial activities, and compounds 2 and 3 showed moderate bioactivity against Staphylococcus aureus (SA) and methicillin-resistant S. aureus (MRSA) with MIC values of 15.8 and 27.1 μM. The results showed that configuration of C-21 in 3 and 4 is important for anti-SA and anti-MRSA activities. This study reveals the significant potential of the genus Chaetomium in producing new PKS-NRPS, therefore increasing the speed in the mining for new sources of antimicrobial agents.

In this study, 102 actinomycetes were isolated from the marine environment from three different locations at Saudi Arabia. Among the actinomycetes isolates, Streptomyces sp. AS11 showed significant activity against methicillin-resistant Staphylococcus aureus (MRSA) was selected for further studies. It has grown well at pH 7.3, 29 °C and with 34% seawater. Based on colony morphology, biochemical, and 16S rDNA sequencing the selected organism was identified as Streptomyces sp. AS11. Among the selected culture medium, ISP4 showed more activity against S. aureus and the zone of inhibition was 29 ± 2 mm. The factors such as, pH and temperature of the culture medium significantly affected secondary metabolite production. Secondary metabolite production was found to be maximum at pH 7.5 (31 ± 1 mm) and marginal decrease in antibiotics production was observed at pH 8.0 (27 ± 1 mm). Antibiotics production was found to be high at 38 °C and the zone of inhibition was 32 ± 2 mm. Among the carbon sources tested, supplementation of glucose and starch enhanced antibiotics production and the zone of inhibition was 31 ± 2 mm and 30 ± 3 mm, respectively. Among the nitrogen sources tested, sodium nitrate enhanced antibiotics production. The secondary metabolite concentration at 2× minimum inhibitory concentration (MIC) and 4× MIC was effectively reduced MRSA. 4× MIC concentration was found to be effective than 2× MIC values and reduced bacterial count considerably. In our study, the crude extract showed cytotoxic effect against cancer cell line and the IC50 value was 0.250 mg/ml. The crude extract acts on HeLa and abnormal cell morphology was observed due to cytotoxic effect. [ABSTRACT FROM AUTHOR]

Kappa-Carrageenan wrapped ZnO nanoparticles (KC-ZnO NPs) was synthesized, physico-chemically characterized and evaluated their biocompatibility and antimicrobial therapy against MRSA. XRD showed the highly crystalline and hexagonal phase structure of ZnO NPs. FETEM confirmed the spherical and hexagonal shaped particle with the mean size of 97.03 ± 9.05 nm. The synthesized KC-ZnO NPs exhibited significant antibacterial activity against MRSA. The biofilm growth of MRSA was greatly inhibited at 100 μg/ml as observed through live and dead cell assay. KC-ZnO NPs have shown invitro anti-inflammatory activity (82%) at 500 μg/ml. KC-ZnO NPs was non-toxic to NIH3T3 mouse embryonic fibroblasts cell lines. Further, no apoptotic and necrotic mediated death in NIH3T3 mouse embryonic fibroblasts cells were noticed by flow cytometric analysis. KC-ZnO NPs have good biocompatibility as recorded by the least hemolysis percentage (<3%) up to 100 μg/ml, which is much lesser than the acceptable limit. In addition, ecosafety analysis has shown that KC-ZnO NPs and kappa karrageenan (0–500 μg/ml) caused no mortality of A. salina after 48 h. However, bare zinc acetate has shown 35% mortality of A. salina after 48 h. The results conclude that KC-ZnO NPs could be a novel antibacterial therapy for the treatment of MRSA associated infectious. Unlabelled Image • Kappa-carrageenan wrapped ZnO NPs (KC-ZNO NPs) was synthesized and characterized. • KC-ZNO NPS showed antibacterial activity against MRSA. • KC-ZNO NPs exhibited anti-inflammatory activity. • KC-ZNO NPs have shown good compatibility with human RBC. • KC-ZNO NPs are non-toxic to A. Salina and are environmentally safe. [ABSTRACT FROM AUTHOR]

Cycloaddition reactions such as intramolecular Diels–Alder (IMDA) are extremely important in constructing multicyclic scaffolds with diverse bioactivities. Using MycB as a biomarker, three new polyketides – Chaetolivacines A (1), B (3), and C (4) – with one known compound Myceliothermophin E (2) comprising of decalin and 4-hydroxy-2-pyridones were obtained from the culture of Chaetomium olivaceum SD-80A under the guidance of gene mining. The structures of these compounds were established using detailed 1D, 2D NMR, and high-resolution electron spray ionization mass spectroscopy (HRESIMS) analysis. The relative and absolute configurations of the compounds 1 , 3 , and 4 were elucidated by NOESY and ECD. The biosynthesis pathways of these compounds were proposed, which involves in three key genes ChaA [polyketide synthase-non-ribosomal peptide synthetases (PKS-NRPS)], ChaB , and ChaC. Compounds 1 – 4 were tested for their antimicrobial activities, and compounds 2 and 3 showed moderate bioactivity against Staphylococcus aureus (SA) and methicillin-resistant S. aureus (MRSA) with MIC values of 15.8 and 27.1 μM. The results showed that configuration of C-21 in 3 and 4 is important for anti-SA and anti-MRSA activities. This study reveals the significant potential of the genus Chaetomium in producing new PKS-NRPS, therefore increasing the speed in the mining for new sources of antimicrobial agents. [ABSTRACT FROM AUTHOR]

Bacterial infections are regarded as one of the leading causes of fatal morbidity and death in patients infected with diseases. The ability of microorganisms, particularly methicillin-resistant Staphylococcus aureus (MRSA), to develop resistance to current drugs has evoked the need for a continuous search for new drugs with better efficacies. Hence, a series of non-PAINS associated pyrrolylated-chalcones (1–15) were synthesized and evaluated for their potency against MRSA. The hydroxyl-containing compounds (8, 9, and 10) showed the most significant anti-MRSA efficiency, with the MIC and MBC values ranging from 0.08 to 0.70 mg/mL and 0.16 to 1.88 mg/mL, respectively. The time-kill curve and SEM analyses exhibited bacterial cell death within four hours after exposure to 9, suggesting its bactericidal properties. Furthermore, the docking simulation between 9 and penicillin-binding protein 2a (PBP2a, PDB ID: 6Q9N) suggests a relatively similar bonding interaction to the standard drug with a binding affinity score of −7.0 kcal/mol. Moreover, the zebrafish model showed no toxic effects in the normal embryonic development, blood vessel formation, and apoptosis when exposed to up to 40 µM of compound 9. The overall results suggest that the pyrrolylated-chalcones may be considered as a potential inhibitor in the design of new anti-MRSA agents.

Biofilms formed by methicillin-resistant S. aureus (MRSA) are among the most frequent causes of biomedical device-related infection, which are difficult to treat and are often persistent and recurrent. Thus, new and effective antibiofilm agents are urgently needed. In this article, we review the most relevant literature of the recent years reporting on promising anti-MRSA biofilm agents derived from the genus Streptomyces bacteria, and discuss the potential contribution of these newly reported antibiofilm compounds to the current strategies in preventing biofilm formation and eradicating pre-existing biofilms of the clinically important pathogen MRSA. Many efforts are evidenced to address biofilm-related infections, and some novel strategies have been developed and demonstrated encouraging results in preclinical studies. Nevertheless, more in vivo studies with appropriate biofilm models and well-designed multicenter clinical trials are needed to assess the prospects of these strategies.

The variability of methicillin-resistant Staphylococcus aureus (MRSA), its rapid adaptive response against environmental changes, and its continued acquisition of antibiotic resistance determinants have made it commonplace in hospitals, where it causes the problem of multidrug resistance. In this study, we used molecular topology to develop several discriminant equations capable of classifying compounds according to their anti-MRSA activity. Topological indices were used as structural descriptors and their relationship with anti-MRSA activity was determined by applying linear discriminant analysis (LDA) on a group of quinolones and quinolone-like compounds. Four extra equations were constructed, named DFMRSA1, DFMRSA2, DFMRSA3 and DFMRSA4 (DFMRSA was built in a previous study), all with good statistical parameters, such as Fisher–Snedecor F (>68 in all cases), Wilk’s lambda (94% in all cases), which allows a reliable extrapolation prediction of antibacterial activity in any organic compound. The results obtained clearly reveal the high efficiency of combining molecular topology with LDA for the prediction of anti-MRSA activity.

Ruta chalepensis L. (Rutaceae), a perennial herb with wild and cultivated habitats, is well known for its traditional uses as an anti-inflammatory, analgesic, antipyretic agent, and in the treatment of rheumatism, nerve diseases, neuralgia, dropsy, convulsions and mental disorders. The antimicrobial activities of the crude extracts from the fruits, leaves, stem and roots of R. chalepensis were initially evaluated against two Gram-positive and two Gram-negative bacterial strains and a strain of the fungus Candida albicans. Phytochemical investigation afforded 19 compounds, including alkaloids, coumarins, flavonoid glycosides, a cinnamic acid derivative and a long-chain alkane. These compounds were tested against a panel of methicillin-resistant Staphylococcus aureus (MRSA) strains, i.e., ATCC 25923, SA-1199B, XU212, MRSA-274819 and EMRSA-15. The MIC values of the active compounds, chalepin (9), chalepensin (10), rutamarin (11), rutin 3′-methyl ether (14), rutin 7,4′-dimethyl ether (15), 6-hydroxy-rutin 3′,7-dimethyl ether (16) and arborinine (18) were in the range of 32–128 µg/mL against the tested MRSA strains. Compounds 10 and 16 were the most active compounds from R. chalepensis, and were active against four out of six tested MRSA strains, and in silico studies were performed on these compounds. The anti-MRSA activity of compound 16 was comparable to that of the positive control norfloxacin (MICs 32 vs 16 μg/mL, respectively) against the MRSA strain XU212, which is a Kuwaiti hospital isolate that possesses the TetK tetracycline efflux pump. This is the first report on the anti-MRSA property of compounds isolated from R. chalepensis and relevant in silico studies on the most active compounds.

There is an urgent need to search for new antibiotics to counter the growing number of antibiotic-resistant bacterial strains, one of which is methicillin-resistant Staphylococcus aureus (MRSA). Herein, we report a Streptomyces sp. strain MUSC 125 from mangrove soil in Malaysia which was identified using 16S rRNA phylogenetic and phenotypic analysis. The methanolic extract of strain MUSC 125 showed anti-MRSA, anti-biofilm and antioxidant activities. Strain MUSC 125 was further screened for the presence of secondary metabolite biosynthetic genes. Our results indicated that both polyketide synthase (pks) gene clusters, pksI and pksII, were detected in strain MUSC 125 by PCR amplification. In addition, gas chromatography-mass spectroscopy (GC-MS) detected the presence of different chemicals in the methanolic extract. Based on the GC-MS analysis, eight known compounds were detected suggesting their contribution towards the anti-MRSA and anti-biofilm activities observed. Overall, the study bolsters the potential of strain MUSC 125 as a promising source of anti-MRSA and antibiofilm compounds and warrants further investigation.

Twenty-four cannabinoids active against MRSA SA1199B and XU212 were optimized at WB97XD/6-31G(d,p), and several molecular descriptors were obtained. Using a multiple linear regression method, several mathematical models with statistical significance were obtained. The robustness of the models was validated, employing the leave-one-out cross-validation and Y-scrambling methods. The entire data set was docked against penicillin-binding protein, iso-tyrosyl tRNA synthetase, and DNA gyrase. The most active cannabinoids had high affinity to penicillin-binding protein (PBP), whereas the least active compounds had low affinities for all of the targets. Among the cannabinoid compounds, Cannabinoid 2 was highlighted due to its suitable combination of both antimicrobial activity and higher scoring values against the selected target; therefore, its docking performance was compared to that of oxacillin, a commercial PBP inhibitor. The 2D figures reveal that both compounds hit the protein in the active site with a similar type of molecular interaction, where the hydroxyl groups in the aromatic ring of cannabinoids play a pivotal role in the biological activity. These results provide some evidence that the anti-Staphylococcus aureus activity of these cannabinoids may be related to the inhibition of the PBP protein; besides, the robustness of the models along with the docking and Quantitative Structure–Activity Relationship (QSAR) results allow the proposal of three new compounds; the predicted activity combined with the scoring values against PBP should encourage future synthesis and experimental testing.

In view of the fast depleting armamentarium of drugs against significant pathogens, like methicillin-resistant Staphylococcus aureus (MRSA) and others due to rapidly emerging drug-resistance, the discovery and development of new drugs need urgent action. In this endeavor, a new strain of endophytic actinobacterium was isolated from the plant Datura metel, which produced secondary metabolites with potent anti-infective activities. The isolate was identified as Streptomyces californicus strain ADR1 based on 16S rRNA gene sequence analysis. Metabolites produced by the isolate had been investigated for their antibacterial attributes against important pathogens: S. aureus, MRSA, S. epidermis, Enterococcus faecium and E. faecalis. Minimum inhibitory concentration (MIC90) values against these pathogens varied from 0.23 ± 0.01 to 5.68 ± 0.20 μg/mL. The metabolites inhibited biofilm formation by the strains of S. aureus and MRSA (Biofilm inhibitory concentration [BIC90] values: 0.74 ± 0.08–4.92 ± 0.49 μg/mL). The BIC90 values increased in the case of pre-formed biofilms. Additionally, the metabolites possessed good antioxidant properties, with an inhibitory concentration (IC90) value of 217.24 ± 6.77 µg/mL for 1, 1-diphenyl-2-picrylhydrazyl (DPPH) free radical scavenging. An insight into different classes of compounds produced by the strain ADR1 was obtained by chemical profiling and GC-MS analysis, wherein several therapeutic classes, for example, alkaloids, phenolics, terpenes, terpenoids and glycosides, were discovered.

Methicillin-resistant Staphylococcus aureus (MRSA) pose a significant health threat as they tend to cause severe infections in vulnerable populations and are difficult to treat due to a limited range of effective antibiotics and also their ability to form biofilm. These organisms were once limited to hospital acquired infections but are now widely present in the community and even in animals. Furthermore, these organisms are constantly evolving to develop resistance to more antibiotics. This results in a need for new clinically useful antibiotics and one potential source are the Streptomyces which have already been the source of several anti-MRSA drugs including vancomycin. There remain large numbers of Streptomyces potentially undiscovered in underexplored regions such as mangrove, deserts, marine, and freshwater environments as well as endophytes. Organisms from these regions also face significant challenges to survival which often result in the production of novel bioactive compounds, several of which have already shown promise in drug development. We review the various mechanisms of antibiotic resistance in MRSA and all the known compounds isolated from Streptomyces with anti-MRSA activity with a focus on those from underexplored regions. The isolation of the full array of compounds Streptomyces are potentially capable of producing in the laboratory has proven a challenge, we also review techniques that have been used to overcome this obstacle including genetic cluster analysis. Additionally, we review the in vivo work done thus far with promising compounds of Streptomyces origin as well as the animal models that could be used for this work.

An unusual meroterpenoid, dysidinoid A (1), was isolated from the South China Sea sponge Dysidea sp. Its structure was elucidated by extensive spectroscopic methods including HRESIMS and 2D NMR, and its absolute configuration was determined by single-crystal X-ray diffraction analysis. Dysidinoid A (1) is the first meroterpenoid from Nature bearing a 9,4-friedodrime skeleton and a 2,5-dionepyrrole unit. Dysidinoid A (1) showed potent antibacterial activity against two strains of pathogenic bacteria methicillin-resistant Staphylococcus aureus (MRSA) with MIC90 values of 8.0 μg/mL against both.

Methicillin-resistant Staphylococcus aureus (MRSA) pose a significant health threat as they tend to cause severe infections in vulnerable populations and are difficult to treat due to a limited range of effective antibiotics and also their ability to form biofilm. These organisms were once limited to hospital acquired infections but are now widely present in the community and even in animals. Furthermore, these organisms are constantly evolving to develop resistance to more antibiotics. This results in a need for new clinically useful antibiotics and one potential source are the Streptomyces which have already been the source of several anti-MRSA drugs including vancomycin. There remain large numbers of Streptomyces potentially undiscovered in underexplored regions such as mangrove, deserts, marine, and freshwater environments as well as endophytes. Organisms from these regions also face significant challenges to survival which often result in the production of novel bioactive compounds, several of which have already shown promise in drug development. We review the various mechanisms of antibiotic resistance in MRSA and all the known compounds isolated from Streptomyces with anti-MRSA activity with a focus on those from underexplored regions. The isolation of the full array of compounds Streptomyces are potentially capable of producing in the laboratory has proven a challenge, we also review techniques that have been used to overcome this obstacle including genetic cluster analysis. Additionally, we review the in vivo work done thus far with promising compounds of Streptomyces origin as well as the animal models that could be used for this work. [ABSTRACT FROM AUTHOR]

Heterologous expression of the type III polyketide synthase (PKS) gene vioA in marine-derived Streptomyces youssoufiensis OUC6819 led to production of six violapyrones (VLPs), including four novel compounds VLPs Q–T ( 1 – 4 ) and two known compounds VLPs B and I ( 5 and 6) . The structures of 1 – 4 were elucidated by a combination of spectroscopic analyses, including HR-ESIMS and 1D and 2D NMR data, demonstrating that 1 – 4 are novel VLPs which are methylated at 4-OH with their corresponding non-methylated counterparts to be VLP A, 5 and 6 and VLP C, respectively. Anti-influenza A [H1N1 (A/Virginia/ATCC1/2009) and H3N2 (A/Aichi/2/1968)] virus activity of compounds 1 – 6 as well as VLPs A and C were then evaluated using ribavirin as a positive control (IC 50  = 66.7 and 99.6 μM). The results revealed that these VLPs showed considerable anti-H1N1 and anti-H3N2 activities with IC 50 values of 30.6–132.4 μM and 45.3–150.0 μM, respectively. Notably, all the methylated VLPs displayed better anti-virus activity than their non-methylated counterparts, among which compound 3 (VLP S) exhibited the best activities. Interestingly, methylation at 4-OH has negative effect on the anti-MRSA (methicillin-resistant Staphylococcus aureus ) activity instead, with methylated VLPs displaying decreased ( 2 ) or abolished ( 3 and 4 ) activities in comparison with each of their non-methylated counterparts. [ABSTRACT FROM AUTHOR]

Bacterial pathogens that colonize wounds form biofilms, which protect the bacteria from the effect of host immune response and antibiotics. This study examined the effectiveness of newly synthesized zinc sulfide in inhibiting biofilm development by Staphylococcus aureus (S. aureus) strains. Zinc sulfide (ZnS) was anaerobically biosynthesized to produce CompA, which was further processed by cryomilling to maximize the antibacterial properties to produce CompB. The effect of the two compounds on the S. aureus strain AH133 was compared using zone of inhibition assay. The compounds were formulated in a polyethylene glycol cream. We compared the effect of the two compounds on biofilm development by AH133 and two methicillin-resistant S. aureus clinical isolates using the in vitro model of wound infection. Zone of inhibition assay revealed that CompB is more effective than CompA. At 15 mg/application, the formulated cream of either compound inhibited biofilm development by AH133, which was confirmed using confocal laser scanning microscopy. At 20 mg/application, CompB inhibited biofilm development by the two methicillin-resistant S. aureus clinical isolates. To further validate the effectiveness of CompB, mice were treated using the murine model of wound infection. Colony forming cell assay and in vivo live imaging results strongly suggested the inhibition of S. aureus growth. [ABSTRACT FROM AUTHOR]