外排泵调节引起的抗菌素耐药性程度,ACS Infectious Diseases

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外排泵调节引起的抗菌素耐药性程度
ACS Infectious Diseases ( IF 4.0 ) Pub Date : 2022-10-20 , DOI: 10.1021/acsinfecdis.2c00460
Vinay Barnabas ₁ , Akanksha Kashyap ₁ , Rubesh Raja ₂ , Kapil Newar ₂ , Deepika Rai ₁ , Narendra M Dixit _{2,

3} , Sarika Mehra ₁

Affiliation

驱动抗菌素耐药性 (AMR) 的一个关键机制源于细菌在接触药物后上调外排泵的能力。由于流出泵水平的严格调节，这种上调获得的阻力是柔韧的。由于在抗生素存在下更高的外排泵水平，这导致细菌的生存能力暂时增强，当细胞不再暴露于药物时可以逆转。由此获得的耐药程度的知识将为旨在减轻 AMR 的干预策略提供信息。在这里，我们结合数学建模和实验来量化外排泵上调可以在药物存在和基因型废除调节的情况下通过表型诱导赋予的最大阻力。我们的模型描述了药物进出细胞的动态变化以及外排泵水平的相关调节，并预测了由于这种调节而导致的药物最小抑制浓度 (MIC) 的增加。为了测试该模型，我们测量了野生型中外排泵 LfrA 的底物溴化乙锭 (EtBr) 的吸收和外排以及 MIC耻垢分枝杆菌mc ² 155，以及两个实验室产生的菌株。我们的模型定量捕获了观察到的 EtBr 水平和 MIC 倍数变化。此外，该模型确定了与产生的耐药性相关的关键参数，其中的变化可能是这种耐药性在不同药物-细菌组合中产生的程度的基础，可能提供可调处理以优化旨在最大限度地减少 AMR 的干预措施。

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The Extent of Antimicrobial Resistance Due to Efflux Pump Regulation

A key mechanism driving antimicrobial resistance (AMR) stems from the ability of bacteria to up-regulate efflux pumps upon exposure to drugs. The resistance gained by this up-regulation is pliable because of the tight regulation of efflux pump levels. This leads to temporary enhancement in survivability of bacteria due to higher efflux pump levels in the presence of antibiotics, which can be reversed when the cells are no longer exposed to the drug. Knowledge of the extent of resistance thus gained would inform intervention strategies aimed at mitigating AMR. Here, we combine mathematical modeling and experiments to quantify the maximum extent of resistance that efflux pump up-regulation can confer via phenotypic induction in the presence of drugs and genotypic abrogation of regulation. Our model describes the dynamics of drug transport in and out of cells coupled with the associated regulation of efflux pump levels and predicts the increase in the minimum inhibitory concentration (MIC) of drugs due to such regulation. To test the model, we measured the uptake and efflux as well as the MIC of the compound ethidium bromide (EtBr), a substrate of the efflux pump LfrA, in wild-type Mycobacterium smegmatis mc²155, as well as in two laboratory-generated strains. Our model captured the observed EtBr levels and MIC fold-changes quantitatively. Further, the model identified key parameters associated with the resulting resistance, variations in which could underlie the extent to which such resistance arises across different drug–bacteria combinations, potentially offering tunable handles to optimize interventions aimed at minimizing AMR.

更新日期：2022-10-20

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