9 results on '"Anthony Simon Lynch"'
Search Results
2. Design, Synthesis, and Characterization of TNP-2198, a Dual-Targeted Rifamycin-Nitroimidazole Conjugate with Potent Activity against Microaerophilic and Anaerobic Bacterial Pathogens
- Author
-
Zhenkun Ma, Shijie He, Ying Yuan, Zhijun Zhuang, Yu Liu, Huan Wang, Jing Chen, Xiangyi Xu, Charles Ding, Vadim Molodtsov, Wei Lin, Gregory T. Robertson, William J. Weiss, Mark Pulse, Phung Nguyen, Leonard Duncan, Timothy Doyle, Richard H. Ebright, and Anthony Simon Lynch
- Subjects
Helicobacter pylori ,Nitroimidazoles ,Drug Discovery ,Molecular Medicine ,Humans ,Anaerobiosis ,DNA-Directed RNA Polymerases ,Rifamycins ,Helicobacter Infections - Abstract
TNP-2198, a stable conjugate of a rifamycin pharmacophore and a nitroimidazole pharmacophore, has been designed, synthesized, and evaluated as a novel dual-targeted antibacterial agent for the treatment of microaerophilic and anaerobic bacterial infections. TNP-2198 exhibits greater activity than a 1:1 molar mixture of the parent drugs and exhibits activity against strains resistant to both rifamycins and nitroimidazoles. A crystal structure of TNP-2198 bound to a
- Published
- 2022
3. Synergistic Activity of Nitroimidazole-Oxazolidinone Conjugates against Anaerobic Bacteria
- Author
-
Yu Lu, Zhuang Zhijun, Charles Z. Ding, Anthony Simon Lynch, Christopher B. Cooper, Wang Xiaomei, Ding Jun, William A. Denny, Zhenkun Ma, Ying Yuan, Wan Dawei, Qian Zhang, Anna M. Upton, and Shijie He
- Subjects
Antitubercular Agents ,Pharmaceutical Science ,synergy ,Drug resistance ,Article ,Analytical Chemistry ,Microbiology ,lcsh:QD241-441 ,Mycobacterium tuberculosis ,03 medical and health sciences ,chemistry.chemical_compound ,Bacteria, Anaerobic ,0302 clinical medicine ,lcsh:Organic chemistry ,Drug Resistance, Multiple, Bacterial ,Drug Discovery ,Tuberculosis, Multidrug-Resistant ,Humans ,nitroimidazole and oxazolidinone ,Physical and Theoretical Chemistry ,Oxazolidinones ,030304 developmental biology ,0303 health sciences ,Nitroimidazole ,biology ,Bicyclic molecule ,Organic Chemistry ,Linezolid ,Drug Synergism ,Antimicrobial ,biology.organism_classification ,chemistry ,Chemistry (miscellaneous) ,Nitroimidazoles ,030220 oncology & carcinogenesis ,Pretomanid ,drug conjugates ,Molecular Medicine ,anaerobic bacterium ,Anaerobic bacteria - Abstract
The introductions of the bicyclic 4-nitroimidazole and the oxazolidinone classes of antimicrobial agents represented the most significant advancements in the infectious disease area during the past two decades. Pretomanid, a bicyclic 4-nitroimidazole, and linezolid, an oxazolidinone, are also part of a combination regimen approved recently by the US Food and Drug Administration for the treatment of pulmonary, extensively drug resistant (XDR), treatment-intolerant or nonresponsive multidrug-resistant (MDR) Mycobacterium tuberculosis (TB). To identify new antimicrobial agents with reduced propensity for the development of resistance, a series of dual-acting nitroimidazole-oxazolidinone conjugates were designed, synthesized and evaluated for their antimicrobial activity. Compounds in this conjugate series have shown synergistic activity against a panel of anaerobic bacteria, including those responsible for serious bacterial infections.
- Published
- 2020
4. Identification of biologic agents to neutralize the bicomponent leukocidins of Staphylococcus aureus
- Author
-
Jeffrey Fernandez, Anthony Simon Lynch, Rita Chan, William R. Strohl, Victor J. Torres, Angela Payne, William E. Sause, Aidan O’Malley, Ashira Lubkin, Brian Whitaker, Kristina M. Boguslawski, Francis Alonzo, and Peter T. Buckley
- Subjects
0301 basic medicine ,030106 microbiology ,Virulence ,General Medicine ,Biology ,medicine.disease_cause ,Staphylococcal infections ,medicine.disease ,Microbiology ,03 medical and health sciences ,Cytolysis ,030104 developmental biology ,Immune system ,Staphylococcus aureus ,In vivo ,medicine ,Pathogen ,Ex vivo - Abstract
A key aspect underlying the severity of infections caused by Staphylococcus aureus is the abundance of virulence factors that the pathogen uses to thwart critical components of the human immune response. One such mechanism involves the destruction of host immune cells by cytolytic toxins secreted by S. aureus, including five bicomponent leukocidins: PVL, HlgAB, HlgCB, LukED, and LukAB. Purified leukocidins can lyse immune cells ex vivo, and systemic injections of purified LukED or HlgAB can acutely kill mice. Here, we describe the generation and characterization of centyrins that bind S. aureus leukocidins with high affinity and protect primary human immune cells from toxin-mediated cytolysis. Centyrins are small protein scaffolds derived from the fibronectin type III-binding domain of the human protein tenascin-C. Although centyrins are potent in tissue culture assays, their short serum half-lives limit their efficacies in vivo. By extending the serum half-lives of centyrins through their fusion to an albumin-binding consensus domain, we demonstrate the in vivo efficacy of these biologics in a murine intoxication model and in models of both prophylactic and therapeutic treatment of live S. aureus systemic infections. These biologics that target S. aureus virulence factors have potential for treating and preventing serious staphylococcal infections.
- Published
- 2019
5. Staphylococcus aureus Strain Newman D2C Contains Mutations in Major Regulatory Pathways That Cripple Its Pathogenesis
- Author
-
Rita Chan, Brian J. Morrow, William E. Sause, Jeffrey Fernandez, Anthony Simon Lynch, Aidan O’Malley, Richard Copin, Bo Shopsin, Victor J. Torres, and Peter T. Buckley
- Subjects
0301 basic medicine ,Staphylococcus aureus ,030106 microbiology ,Virulence ,Human pathogen ,Disease ,Biology ,medicine.disease_cause ,Microbiology ,Polymorphism, Single Nucleotide ,03 medical and health sciences ,Bacterial Proteins ,medicine ,Molecular Biology ,Loss function ,Regulator gene ,Mutation ,Whole Genome Sequencing ,Gene Expression Regulation, Bacterial ,Complementation ,Genome, Bacterial ,Research Article ,Transcription Factors - Abstract
Staphylococcus aureus is a major human pathogen that imposes a great burden on the health care system. In the development of antistaphylococcal modalities intended to reduce the burden of staphylococcal disease, it is imperative to select appropriate models of S. aureus strains when assessing the efficacy of novel agents. Here, using whole-genome sequencing, we reveal that the commonly used strain Newman D2C from the American Type Culture Collection (ATCC) contains mutations that render the strain essentially avirulent. Importantly, Newman D2C is often inaccurately referred to as simply “Newman” in many publications, leading investigators to believe it is the well-described pathogenic strain Newman. This study reveals that Newman D2C carries a stop mutation in the open reading frame of the virulence gene regulator, agrA . In addition, Newman D2C carries a single-nucleotide polymorphism (SNP) in the global virulence regulator gene saeR that results in loss of protein function. This loss of function is highlighted by complementation studies, where the saeR allele from Newman D2C is incapable of restoring functionality to an saeR -null mutant. Additional functional assessment was achieved through the use of biochemical assays for protein secretion, ex vivo intoxications of human immune cells, and in vivo infections. Altogether, our study highlights the importance of judiciously screening for genetic changes in model S. aureus strains when assessing pathogenesis or the efficacy of novel agents. Moreover, we have identified a novel SNP in the virulence regulator gene saeR that directly affects the ability of the protein product to activate S. aureus virulence pathways. IMPORTANCE Staphylococcus aureus is a human pathogen that imposes an enormous burden on health care systems worldwide. This bacterium is capable of evoking a multitude of disease states that can range from self-limiting skin infections to life-threatening bacteremia. To combat these infections, numerous investigations are under way to develop therapeutics capable of thwarting the deadly effects of the bacterium. To generate successful treatments, it is of paramount importance that investigators use suitable models for examining the efficacy of the drugs under study. Here, we demonstrate that a strain of S. aureus commonly used for drug efficacy studies is severely mutated and displays markedly reduced pathogenicity. As such, the organism is an inappropriate model for disease studies.
- Published
- 2017
6. Staphylococcus aureus Leukocidins Target Endothelial DARC to Cause Lethality in Mice
- Author
-
Jason Aligo, Bo Shopsin, Ashira Lubkin, Matthew D. Keller, Rita Chan, Anthony Simon Lynch, Victor J. Torres, Maryaline Coffre, Daniel Weinstock, Michael Sugiyama, Francis Alonzo rd, Sergei B. Koralov, Eric Chen, Sofia Bajwa, Ken Cadwell, Nikollaq Vozhilla, Johnny Su, G. Scott Worthen, Changsen Wang, Sang Yong Kim, Peter T. Buckley, Natasha M. Girgis, P'ng Loke, Warren L. Lee, Kamal M. Khanna, Patricia Martin, Marilyn T. Vasquez, Cynthia A. Loomis, Stephen T. Yeung, Aidan O’Malley, and Tamara Reyes-Robles
- Subjects
Staphylococcus aureus ,Chemokine ,Cell Survival ,Bacterial Toxins ,Leukocidin ,Exotoxins ,Virulence ,Receptors, Cell Surface ,medicine.disease_cause ,Models, Biological ,Microbiology ,Article ,Pathogenesis ,Hemolysin Proteins ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Bacterial Proteins ,Leukocidins ,Virology ,medicine ,Humans ,Animals ,Endothelium ,Cells, Cultured ,030304 developmental biology ,Mice, Knockout ,0303 health sciences ,biology ,Toxin ,Organ dysfunction ,Endothelial Cells ,Staphylococcal Infections ,Survival Analysis ,3. Good health ,Disease Models, Animal ,Immunology ,biology.protein ,Parasitology ,Lethality ,medicine.symptom ,Duffy Blood-Group System ,030217 neurology & neurosurgery - Abstract
Summary The pathogenesis of Staphylococcus aureus is thought to depend on the production of pore-forming leukocidins that kill leukocytes and lyse erythrocytes. Two leukocidins, Leukocidin ED (LukED) and γ-Hemolysin AB (HlgAB), are necessary and sufficient to kill mice upon infection and toxin challenge. We demonstrate that LukED and HlgAB cause vascular congestion and derangements in vascular fluid distribution that rapidly cause death in mice. The Duffy antigen receptor for chemokines (DARC) on endothelial cells, rather than leukocytes or erythrocytes, is the critical target for lethality. Consistent with this, LukED and HlgAB injure primary human endothelial cells in a DARC-dependent manner, and mice with DARC-deficient endothelial cells are resistant to toxin-mediated lethality. During bloodstream infection in mice, DARC targeting by S. aureus causes increased tissue damage, organ dysfunction, and host death. The potential for S. aureus leukocidins to manipulate vascular integrity highlights the importance of these virulence factors.
- Published
- 2019
7. Development of a Dual-Acting Antibacterial Agent (TNP-2092) for the Treatment of Persistent Bacterial Infections
- Author
-
Zhenkun Ma and Anthony Simon Lynch
- Subjects
0301 basic medicine ,Drug ,Staphylococcus aureus ,medicine.drug_class ,media_common.quotation_subject ,030106 microbiology ,Antibiotics ,Rifamycins ,Microbial Sensitivity Tests ,medicine.disease_cause ,Microbiology ,03 medical and health sciences ,Structure-Activity Relationship ,Drug Discovery ,polycyclic compounds ,medicine ,media_common ,Antibacterial agent ,biology ,Dose-Response Relationship, Drug ,Molecular Structure ,Drug candidate ,Rifamycin ,Bacterial Infections ,biology.organism_classification ,Anti-Bacterial Agents ,030104 developmental biology ,Molecular Medicine ,Bacteria - Abstract
The clinical management of prosthetic joint infections and other persistent bacterial infections represents a major unmet medical need. The rifamycins are one of the most potent antibiotic classes against persistent bacterial infections, but bacteria can develop resistance to rifamycins rapidly and the clinical utility of the rifamycin class is typically limited to antibiotic combinations to minimize the development of resistance. To develop a better therapy against persistent bacterial infections, a series of rifamycin based bifunctional molecules were designed, synthesized, and evaluated with the goal to identify a dual-acting drug that maintains the potent activity of rifamycins against persistent pathogens and at the same time minimize the development of rifamycin resistance. TNP-2092 was identified as a drug candidate and is currently in an early stage of clinical development for the treatment of prosthetic joint infections.
- Published
- 2016
8. Assessment of the combination of doripenem plus a fluoroquinolone against non-susceptible Acinetobacter baumannii isolates from nosocomial pneumonia patients
- Author
-
Anne Marie Queenan, Anthony Simon Lynch, Todd A. Davies, and Wenping He
- Subjects
Acinetobacter baumannii ,Ofloxacin ,Combination therapy ,Cmax ,Levofloxacin ,Microbiology ,Mice ,Random Allocation ,In vivo ,Ciprofloxacin ,medicine ,Animals ,Pharmacology (medical) ,Pharmacology ,biology ,Dose-Response Relationship, Drug ,business.industry ,Doripenem ,Pneumonia, Ventilator-Associated ,Drug Synergism ,biochemical phenomena, metabolism, and nutrition ,bacterial infections and mycoses ,medicine.disease ,biology.organism_classification ,Survival Analysis ,Drug Resistance, Multiple ,Pneumonia ,Infectious Diseases ,Oncology ,Carbapenems ,Drug Therapy, Combination ,Female ,business ,medicine.drug ,Acinetobacter Infections - Abstract
Carbapenem- and fluoroquinolone-non-susceptible Acinetobacter baumannii were obtained from four nosocomial pneumonia patients who were clinically cured following combination therapy with doripenem/levofloxacin or ciprofloxacin. In vitro synergy of doripenem/levofloxacin or ciprofloxacin was evaluated using time-kill analysis. In vivo synergy was tested using a mouse lethal infection model. In time-kill studies, doripenem and levofloxacin were both bactericidal when tested at Cmax; at ½Cmax, the combination showed synergy up to 8 hours. Ciprofloxacin, alone or combined with doripenem, was not bactericidal. For mouse septicemia, doripenem (100 mg/kg) was ≥90% effective in preventing death in all four isolates. Levofloxacin (200 mg/kg) was 73% effective, and ciprofloxacin (35 mg/kg) was ineffective in preventing death. At lower drug concentrations, increased efficacy was observed for doripenem/levofloxacin, but not for doripenem/ciprofloxacin. Overall, the results suggest that a doripenem/levofloxacin combination may have clinical utility in treating some non-susceptible A. baumannii infections.
- Published
- 2013
9. New C25 carbamate rifamycin derivatives are resistant to inactivation by ADP-ribosyl transferases
- Author
-
Eric D. Roche, Dalai Yan, Eric J. Bonventre, Anthony Simon Lynch, Timothy B Doyle, Daniel Denton, Gregory T. Robertson, Keith D. Combrink, Katrina Chapo, Susan Harran, and Zhenkun Ma
- Subjects
Carbamate ,Staphylococcus aureus ,Magnetic Resonance Spectroscopy ,Stereochemistry ,medicine.medical_treatment ,Clinical Biochemistry ,Mycobacterium smegmatis ,Pharmaceutical Science ,Rifamycins ,Microbial Sensitivity Tests ,medicine.disease_cause ,Biochemistry ,Structure-Activity Relationship ,Drug Discovery ,Drug Resistance, Bacterial ,polycyclic compounds ,medicine ,Escherichia coli ,Transferase ,Molecular Biology ,chemistry.chemical_classification ,ADP Ribose Transferases ,biology ,Chemistry ,Organic Chemistry ,Rifamycin ,biology.organism_classification ,Anti-Bacterial Agents ,Enzyme ,Pseudomonas aeruginosa ,Molecular Medicine ,Rifampin ,Pentosyltransferases - Abstract
A novel series of 3-morpholino rifamycins in which the C25 acetate group was replaced by a carbamate group were prepared and found to exhibit significantly improved antimicrobial activity than rifampin against Mycobacterium smegmatis. Further characterization of such compounds suggests that relatively large groups attached to the rifamycin core via a C25 carbamate linkage prevent inactivation via ribosylation of the C23 alcohol as catalyzed by the endogenous rifampin ADP-ribosyl transferase of M. smegmatis. SAR studies of the C25 carbamate rifamycin series against M. smegmatis and other bacteria are reported.
- Published
- 2006
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.