The number of antibiotic resistant pathogens is increasing rapidly, and with this comes a substantial socioeconomic cost that threatens much of the world. To alleviate this problem, we must use antibiotics in a more responsible and informed way, further our understanding of the molecular basis of drug resistance, and design new antibiotics. Here, we focus on a key drug‐resistant pathogen, Mycobacterium tuberculosis, and computationally analyze trends in drug‐resistant mutations in genes of the proteins embA, embB, embC, and katG, which play essential roles in the action of the first‐line drugs ethambutol and isoniazid. We use docking to predict binding modes of isoniazid to katG that agree with suggested binding sites found in our laboratory using cryo‐EM. Using mutant stability predictions, we recapitulate the idea that resistance occurs when katG's heme cofactor is destabilized rather than due to a decrease in affinity to isoniazid. Conversely, we have identified resistance mutations that affect the affinity of ethambutol more drastically than the affinity of the natural substrate of embB. With this, we illustrate that we can distinguish between the two types of drug resistance—cofactor destabilization and drug affinity reduction—suggesting potential uses in the prediction of novel drug‐resistant mutations.

中文翻译：

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结核分枝杆菌 katG 和 emb 复合物耐药突变的计算分析

抗生素耐药性病原体的数量正在迅速增加，随之而来的是巨大的社会经济成本，威胁着世界大部分地区。为了缓解这一问题，我们必须以更负责任和更明智的方式使用抗生素，进一步了解耐药性的分子基础，并设计新的抗生素。在这里，我们重点关注一种关键的耐药病原体，结核分枝杆菌，并通过计算分析蛋白质基因耐药突变的趋势工商管理硕士,嵌入B,胚胎干细胞， 和卡特G，在一线药物乙胺丁醇和异烟肼的作用中发挥重要作用。我们使用对接来预测异烟肼与卡特G与我们实验室使用冷冻电镜发现的建议结合位点一致。使用突变体稳定性预测，我们概括了这样的想法：当卡特格的血红素辅因子不稳定，而不是由于与异烟肼的亲和力降低。相反，我们已经鉴定出抗性突变对乙胺丁醇的亲和力的影响比对乙胺丁醇天然底物的亲和力的影响更大。嵌入B。由此，我们说明我们可以区分两种类型的耐药性——辅因子不稳定和药物亲和力降低——这表明在预测新型耐药突变方面具有潜在用途。