Bayesian Modeling and Intrabacterial Drug Metabolism Applied to Drug-Resistant Staphylococcus aureus

We present the application of Bayesian modeling to identify chemical tools and/or drug discovery entities pertinent to drug-resistant Staphylococcus aureus infections. The quinoline JSF-3151 was predicted by modeling and then empirically demonstrated to be active against in vitro cultured clinical methicillin- and vancomycin-resistant strains while also exhibiting efficacy in a mouse peritonitis model of methicillin-resistant S. aureus infection. We highlight the utility of an intrabacterial drug metabolism (IBDM) approach to probe the mechanism by which JSF-3151 is transformed within the bacteria. We also identify and then validate two mechanisms of resistance in S. aureus: one mechanism involves increased expression of a lipocalin protein, and the other arises from the loss of function of an azoreductase. The computational and experimental approaches, discovery of an antibacterial agent, and elucidated resistance mechanisms collectively hold promise to advance our understanding of therapeutic regimens for drug-resistant S. aureus.

Medienart:

E-Artikel

Erscheinungsjahr:

2021

Erschienen:

2021

Enthalten in:

Zur Gesamtaufnahme - volume:7

Enthalten in:

ACS infectious diseases - 7(2021), 8 vom: 13. Aug., Seite 2508-2521

Sprache:

Englisch

Beteiligte Personen:

Patel, Jimmy S [VerfasserIn]
Norambuena, Javiera [VerfasserIn]
Al-Tameemi, Hassan [VerfasserIn]
Ahn, Yong-Mo [VerfasserIn]
Perryman, Alexander L [VerfasserIn]
Wang, Xin [VerfasserIn]
Daher, Samer S [VerfasserIn]
Occi, James [VerfasserIn]
Russo, Riccardo [VerfasserIn]
Park, Steven [VerfasserIn]
Zimmerman, Matthew [VerfasserIn]
Ho, Hsin-Pin [VerfasserIn]
Perlin, David S [VerfasserIn]
Dartois, Véronique [VerfasserIn]
Ekins, Sean [VerfasserIn]
Kumar, Pradeep [VerfasserIn]
Connell, Nancy [VerfasserIn]
Boyd, Jeffrey M [VerfasserIn]
Freundlich, Joel S [VerfasserIn]

Links:

Volltext

Themen:

AzoR
Bayesian modeling
Intrabacterial drug metabolism
Journal Article
Pharmaceutical Preparations
Quinoline
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.
Staphylococcus aureus
YceI

Anmerkungen:

Date Completed 09.09.2021

Date Revised 14.08.2022

published: Print-Electronic

Citation Status MEDLINE

doi:

10.1021/acsinfecdis.1c00265

funding:

Förderinstitution / Projekttitel:

PPN (Katalog-ID):

NLM328869201