Transient Silencing of Antibiotic Resistance by Mutation Represents a Significant Potential Source of Unanticipated Therapeutic Failure
Transient Silencing of Antibiotic Resistance by Mutation Represents a Significant Potential Source of Unanticipated Therapeutic Failure
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DOI：
10.1128/mbio.01755-19
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发表时间：
2019-09-01
期刊：
影响因子：
6.4
通讯作者：
O'Neill, Alex J.
中科院分区：
文献类型：
--
作者：
Kime, Louise;Randall, Christopher P.;O'Neill, Alex J.
零星的文献报道描述了病原细菌的分离，其中含有抗生素耐药性决定因素，但由于遗传缺陷，仍然对相应的抗生素敏感。这些菌株代表了抗生素耐药性可能重新出现的来源，从而导致患者治疗失败。在这里，我们报告了对这种现象的普遍性和性质的系统调查，我们称之为突变抗生素耐药性沉默（SARM）。通过并排比较抗生素耐药基因型（由全基因组测序确定）与表型（通过药敏试验评估），在1,470株金黄色葡萄球菌中检测到SARM病例。在分析的分离株中，152株（10.3%）携带沉默耐药基因，其中46株（3.1%）对目前使用的抗葡萄球菌药物表现出SARM。SARM是由多种突变事件引起的，但最常见的是由于多聚a链的点缺失导致抗性决定因素的移码突变。大多数SARM菌株（接近90%）在频率为>= 10（-9）时恢复耐药性；因此，虽然在临床微生物学实验室中表现出抗生素敏感性，但大多数表现出SARM的金黄色葡萄球菌分离株会以患者可达到的频率恢复抗生素耐药性。鉴于其在主要病原体中的流行，SARM对抗生素的治疗效果构成了重大的潜在威胁。抗生素耐药性阻碍了细菌感染的治疗。为了指导有效的治疗，临床微生物实验室例行进行药敏试验，以确定感染病原体的抗生素敏感性。这种方法依赖于一种假设，即它可以可靠地区分患者体内能够表达抗生素耐药性的细菌，这一想法受到了本研究的挑战。我们报道，重要的人类病原体金黄色葡萄球菌经常携带抗生素耐药基因，这些基因因突变而失活（“沉默”），导致菌株出现抗生素敏感。然而，在大多数此类病例中，耐药性可迅速重新出现，其频率在受感染患者中很容易达到。因此，沉默的抗生素耐药是普遍的，短暂的，并且逃避常规检测，使其成为抗菌化疗的重大潜在威胁。
Sporadic literature reports describe isolates of pathogenic bacteria that harbor an antibiotic resistance determinant but remain susceptible to the corresponding antibiotic as a consequence of a genetic defect. Such strains represent a source from which antibiotic resistance may reemerge to cause treatment failure in patients. Here, we report a systematic investigation into the prevalence and nature of this phenomenon, which we term silencing of antibiotic resistance by mutation (SARM). Instances of SARM were detected among 1,470 Staphylococcus aureus isolates through side-by-side comparison of antibiotic resistance genotype (as determined by whole-genome sequencing) versus phenotype (as assessed through susceptibility testing). Of the isolates analyzed, 152 (10.3%) harbored a silenced resistance gene, including 46 (3.1%) that exhibited SARM to currently deployed antistaphylococcal drugs. SARM resulted from diverse mutational events but most commonly through frameshift mutation of resistance determinants as a result of point deletion in poly(A) tracts. The majority (similar to 90%) of SARM strains reverted to antibiotic resistance at frequencies of >= 10(-9); thus, while appearing antibiotic sensitive in the clinical microbiology laboratory, most S. aureus isolates exhibiting SARM will revert to antibiotic resistance at frequencies achievable in patients. In view of its prevalence in a major pathogen, SARM represents a significant potential threat to the therapeutic efficacy of antibiotics.IMPORTANCE Antibiotic resistance hinders the treatment of bacterial infection. To guide effective therapy, clinical microbiology laboratories routinely perform susceptibility testing to determine the antibiotic sensitivity of an infecting pathogen. This approach relies on the assumption that it can reliably distinguish bacteria capable of expressing antibiotic resistance in patients, an idea challenged by the present study. We report that the important human pathogen Staphylococcus aureus frequently carries antibiotic resistance genes that have become inactivated ("silenced") by mutation, leading strains to appear antibiotic sensitive. However, resistance can rapidly reemerge in most such cases, at frequencies readily achievable in infected patients. Silent antibiotic resistance is therefore prevalent, transient, and evades routine detection, rendering it a significant potential threat to antibacterial chemotherapy.