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.

Automated summary

The study applied Bayesian modeling to identify chemical tools and drug discovery entities for drug-resistant Staphylococcus aureus infections, leading to the discovery of the active quinoline JSF-3151 and investigation of its intrabacterial transformation mechanism. Resistance mechanisms involving increased expression of a lipocalin protein and loss of function of an azoreductase in S. aureus were identified and validated, offering insights for developing therapeutic regimens for drug-resistant S. aureus.