Bayesian Modeling and Intrabacterial Drug Metabolism Applied to Drug-Resistant Staphylococcus aureus,ACS Infectious Diseases

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Bayesian Modeling and Intrabacterial Drug Metabolism Applied to Drug-Resistant Staphylococcus aureus
ACS Infectious Diseases ( IF 4.0 ) Pub Date : 2021-08-03 , DOI: 10.1021/acsinfecdis.1c00265
Jimmy S Patel ₁ , Javiera Norambuena ₂ , Hassan Al-Tameemi ₂ , Yong-Mo Ahn ₁ , Alexander L Perryman ₁ , Xin Wang ₁ , Samer S Daher ₁ , James Occi ₃ , Riccardo Russo ₃ , Steven Park ₄ , Matthew Zimmerman ₄ , Hsin-Pin Ho ₄ , David S Perlin ₄ , Véronique Dartois ₄ , Sean Ekins ₅ , Pradeep Kumar ₃ , Nancy Connell ₃ , Jeffrey M Boyd ₂ , Joel S Freundlich _{1,

3}

Affiliation

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.

中文翻译：

贝叶斯模型和细菌内药物代谢应用于耐药金黄色葡萄球菌

我们介绍了贝叶斯模型在识别与耐药金黄色葡萄球菌感染相关的化学工具和/或药物发现实体方面的应用。喹啉 JSF-3151 通过建模进行预测，然后凭经验证明其对体外培养的临床耐甲氧西林和万古霉素耐药菌株具有活性，同时在耐甲氧西林金黄色葡萄球菌感染的小鼠腹膜炎模型中也表现出疗效。我们强调了细菌内药物代谢 (IBDM) 方法在探索 JSF-3151 在细菌内转化的机制的实用性。我们还确定并验证了金黄色葡萄球菌的两种耐药机制：一种机制涉及脂质运载蛋白的表达增加，另一种机制是由于偶氮还原酶的功能丧失。计算和实验方法、抗菌剂的发现以及阐明的耐药机制共同有望促进我们对耐药金黄色葡萄球菌治疗方案的理解。

更新日期：2021-08-13

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