Genome-wide association studies reveal distinct genetic correlates and increased heritability of antimicrobial resistance in Vibrio cholerae under anaerobic conditions.
Genome-wide association studies reveal distinct genetic correlates and increased heritability of antimicrobial resistance in Vibrio cholerae under anaerobic conditions.
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DOI：
10.1099/mgen.0.000905
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发表时间：
2022-12
影响因子：
3.9
通讯作者：
Nelson, Eric J
中科院分区：
文献类型：
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作者：
Creasy-Marrazzo, Ashton;Saber, Morteza M;Kamat, Manasi;Bailey, Laura S;Brinkley, Lindsey;Cato, Emilee;Begum, Yasmin;Rashid, Md Mahbubur;Khan, Ashraful I;Qadri, Firdausi;Basso, Kari B;Shapiro, B Jesse;Nelson, Eric J
肠道病原体中抗生素耐药性 (AMR) 的高比率威胁着抗生素处方。肠道细菌暴露在胃肠道内的厌氧条件下，但人们对氧气暴露如何影响 AMR 知之甚少。选择兼性厌氧菌霍乱弧菌作为模型来解决这一知识空白。我们从 66 名霍乱患者中分离出霍乱弧菌，对其基因组进行了测序，并在使用或不使用三种临床相关抗生素（环丙沙星、阿奇霉素、多西环素）的厌氧和需氧条件下培养它们。对于环丙沙星和阿奇霉素，与需氧条件相比，厌氧条件下的最低抑菌浓度 (MIC) 有所增加。使用标准耐药断点，与有氧条件相比，在厌氧条件下将分离株分类为耐药的几率对于环丙沙星增加了 10 倍以上，对于阿奇霉素则增加了 100 倍以上。对于强力霉素，几乎所有分离株在这两种条件下均敏感。通过全基因组关联研究，我们发现遗传元件与 AMR 表型之间的关联因氧气暴露和抗生素浓度而异。这些 AMR 表型更具遗传性，并且在厌氧条件下更容易发现与 AMR 相关的遗传元件。这些与 AMR 相关的遗传元件是未来机制研究的有希望的目标。我们的研究结果为确定厌氧条件下 MIC 增加是否与霍乱患者的治疗失败和/或微生物逃逸相关提供了依据。如果是这样，可能需要为厌氧条件确定新的 AMR 断点。
The antibiotic formulary is threatened by high rates of antimicrobial resistance (AMR) among enteropathogens. Enteric bacteria are exposed to anaerobic conditions within the gastrointestinal tract, yet little is known about how oxygen exposure influences AMR. The facultative anaerobe Vibrio cholerae was chosen as a model to address this knowledge gap. We obtained V. cholerae isolates from 66 cholera patients, sequenced their genomes, and grew them under anaerobic and aerobic conditions with and without three clinically relevant antibiotics (ciprofloxacin, azithromycin, doxycycline). For ciprofloxacin and azithromycin, the minimum inhibitory concentration (MIC) increased under anaerobic conditions compared to aerobic conditions. Using standard resistance breakpoints, the odds of classifying isolates as resistant increased over 10 times for ciprofloxacin and 100 times for azithromycin under anaerobic conditions compared to aerobic conditions. For doxycycline, nearly all isolates were sensitive under both conditions. Using genome-wide association studies, we found associations between genetic elements and AMR phenotypes that varied by oxygen exposure and antibiotic concentrations. These AMR phenotypes were more heritable, and the AMR-associated genetic elements were more often discovered, under anaerobic conditions. These AMR-associated genetic elements are promising targets for future mechanistic research. Our findings provide a rationale to determine whether increased MICs under anaerobic conditions are associated with therapeutic failures and/or microbial escape in cholera patients. If so, there may be a need to determine new AMR breakpoints for anaerobic conditions.