Genetic Determinants of Intrinsic Antibiotic Tolerance in Mycobacterium avium.
Genetic Determinants of Intrinsic Antibiotic Tolerance in Mycobacterium avium.
复制标题
鸟分枝杆菌内在抗生素耐受性的遗传决定因素。
DOI：
10.1128/spectrum.00246-21
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发表时间：
2021-10-31
影响因子：
3.7
通讯作者：
Karakousis PC
中科院分区：
文献类型：
--
作者：
Matern WM;Parker H;Danchik C;Hoover L;Bader JS;Karakousis PC
鸟分枝杆菌复合体 (MAC) 是美国非结核分枝杆菌肺部感染最常见的原因之一，但对其的研究仍未充分。目前的 MAC 治疗需要一年多的间歇性到每日联合抗生素治疗，具体取决于疾病的严重程度。为了缩短和简化治疗方案，重要的是确定导致抗生素敏感性降低的先天细菌因素，即抗生素耐受基因。在这项研究中，我们进行了全基因组转座子筛选，以阐明鸟分枝杆菌基因，这些基因在细菌对一线和二线抗生素的耐受性中发挥作用。我们总共鉴定了 193 种独特的鸟分枝杆菌突变体，它们对我们测试的四种临床使用的抗生素中的至少一种的敏感性显着改变，其中包括两种具有全敏感性的突变体（DFS55_00905 和 DFS55_12730）。我们已经确定的抗生素耐受基因的产物可能代表未来药物开发研究的新目标，旨在缩短 MAC 感染的治疗持续时间。重要性 根除鸟分枝杆菌复合体 (MAC) 感染所需的长期治疗可能是由于存在对现有药物敏感性降低的抗生素耐受细菌亚群。然而，人们对 MAC 抗生素耐受性的基因和途径知之甚少。在这项研究中，我们进行了正向遗传筛选，以确定鸟分枝杆菌抗生素耐受基因，其产物可能代表开发能够缩短 MAC 感染治疗时间的新型辅助药物的有吸引力的目标。
The Mycobacterium avium complex (MAC) is one of the most prevalent causes of nontuberculous mycobacteria pulmonary infection in the United States, and yet it remains understudied. Current MAC treatment requires more than a year of intermittent to daily combination antibiotic therapy, depending on disease severity. In order to shorten and simplify curative regimens, it is important to identify the innate bacterial factors contributing to reduced antibiotic susceptibility, namely, antibiotic tolerance genes. In this study, we performed a genome-wide transposon screen to elucidate M. avium genes that play a role in the bacterium’s tolerance to first- and second-line antibiotics. We identified a total of 193 unique M. avium mutants with significantly altered susceptibility to at least one of the four clinically used antibiotics we tested, including two mutants (in DFS55_00905 and DFS55_12730) with panhypersusceptibility. The products of the antibiotic tolerance genes we have identified may represent novel targets for future drug development studies aimed at shortening the duration of therapy for MAC infections. IMPORTANCE The prolonged treatment required to eradicate Mycobacterium avium complex (MAC) infection is likely due to the presence of subpopulations of antibiotic-tolerant bacteria with reduced susceptibility to currently available drugs. However, little is known about the genes and pathways responsible for antibiotic tolerance in MAC. In this study, we performed a forward genetic screen to identify M. avium antibiotic tolerance genes, whose products may represent attractive targets for the development of novel adjunctive drugs capable of shortening the curative treatment for MAC infections.