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

Abstract

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.

Keywords: AzoR; Bayesian modeling; Staphylococcus aureus; YceI; intrabacterial drug metabolism; quinoline.

Figure 1.. IBDM studies of JSF-3151 and JSF-3640.

A) Time course study depicting the intrabacterial accumulation of JSF-3151 within S. aureus strains JMB1100 (WT), yceI2, and azoR::Tn that were treated with JSF-3151. B) Time course study depicting the intrabacterial accumulation of JSF-3640 within S. aureus strains JMB1100 (WT), yceI2, and azoR::Tn that were treated with JSF-3151. C) High-resolution mass spectrometry supports assignment of JSF-3640 as the amine metabolite, formed from JSF-3151, based on its spectral signature.