The emergence of antibiotic genetic resisters of pathogenic bacteria poses a major public health challenge. The mechanism by which bacterial antibiotic genetic resister clones formed de novo multiply and establish a resister population remained unknown. Here, we delineated the unique mode of cell division of the antibiotic genetic resisters of Mycobacterium smegmatis and Mycobacterium tuberculosis formed de novo from the population surviving in the presence of bactericidal concentrations of rifampicin or moxifloxacin. The cells in the rifampicin/moxifloxacin-surviving population generated elevated levels of hydroxyl radical-inflicting mutations. The genetic mutants selected against rifampicin/moxifloxacin became multinucleated and multiseptated and developed multiple constrictions. These cells stochastically divided multiple times, producing sister-daughter cells phenomenally higher in number than what could be expected from their generation time. This caused an abrupt, unexpectedly high increase in the rifampicin/moxifloxacin resister colonies. This unique cell division behavior was not shown by the rifampicin resisters formed naturally in the actively growing cultures. We could detect such abrupt increases in the antibiotic resisters in others’ and our earlier data on the antibiotic-exposed laboratory/clinical M. tuberculosis strains, M. smegmatis and other bacteria in in vitro cultures, infected macrophages/animals, and tuberculosis patients. However, it went unnoticed/unreported in all those studies. This phenomenon occurring in diverse bacteria surviving against different antibiotics revealed the broad significance of the present study. We speculate that the antibiotic-resistant bacillary clones, which emerge in patients with diverse bacterial infections, might be using the same mechanism to establish an antibiotic resister population quickly in the continued presence of antibiotics.

中文翻译：

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从抗生素存活人群中从头出现的分枝杆菌遗传抗性克隆的独特细胞分裂模式

病原菌抗生素遗传抗性的出现对公共卫生构成了重大挑战。细菌抗生素遗传抗性克隆形成从头繁殖并建立抗性种群的机制仍然未知。在这里，我们描绘了耻垢分枝杆菌和结核分枝杆菌从头形成的抗生素遗传抗性的独特细胞分裂模式来自在存在杀菌浓度的利福平或莫西沙星的情况下存活的人群。利福平/莫西沙星存活群体中的细胞产生了升高水平的引起羟基自由基的突变。针对利福平/莫西沙星选择的遗传突变体变成了多核和多分隔并形成了多个收缩。这些细胞随机分裂多次，产生的姊妹细胞数量明显高于其世代预期的数量。这导致利福平/莫西沙星耐药菌落突然、出乎意料地大量增加。这种独特的细胞分裂行为在活跃生长的培养物中自然形成的利福平抗药性没有表现出来。体外培养物中的结核分枝杆菌菌株、耻垢分枝杆菌和其他细菌、感染的巨噬细胞/动物和结核病患者。然而，在所有这些研究中都没有注意到/没有报告。这种现象发生在对不同抗生素存活的不同细菌中，揭示了本研究的广泛意义。我们推测，在各种细菌感染患者中出现的抗生素耐药性细菌克隆可能使用相同的机制在抗生素持续存在的情况下快速建立抗生素耐药群体。