Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore, Karnataka, India.
Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore, Karnataka, India
mSphere. 2020 Nov 18;5(6):e00994-20. doi: 10.1128/mSphere.00994-20.
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 multiply and establish a resister population remained unknown. Here, we delineated the unique mode of cell division of the antibiotic genetic resisters of and formed 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 strains, and other bacteria in 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. The bacterial pathogens that are tolerant to antibiotics and survive in the continued presence of antibiotics have the chance to acquire genetically resistant mutations against the antibiotics and emerge as antibiotic resisters. Once the antibiotic resister clone has emerged, often with compromise on growth characteristics, for the protection of the species, it is important to establish an antibiotic-resistant population quickly in the continued presence of the antibiotic. In this regard, the present study has unraveled multinucleation and multiseptation followed by multiple constrictions as the cellular processes used by the bacteria for quick multiplication to establish antibiotic-resistant populations. The study also points out the same phenomenon occurring in other bacterial systems investigated in our laboratory and others' laboratories. Identification of these specific cellular events involved in quick multiplication offers additional cellular processes that can be targeted in combination with the existing antibiotics' targets to preempt the emergence of antibiotic-resistant bacterial strains.
抗生素耐药性细菌的出现对公共健康构成了重大挑战。细菌抗生素耐药性克隆形成、增殖和建立耐药种群的机制尚不清楚。在这里，我们描述了在杀菌浓度利福平或莫西沙星存在下存活的种群中形成的 和 抗生素耐药性克隆的独特细胞分裂模式。在利福平/莫西沙星存活的群体中，细胞产生高水平的羟基自由基引起的突变。对利福平/莫西沙星有抗性的遗传突变体成为多核和多隔膜，并形成多个收缩。这些细胞随机多次分裂，产生的姐妹细胞数量远远超过其世代时间所预期的数量。这导致利福平/莫西沙星耐药菌落突然、出乎意料地增加。这种独特的细胞分裂行为在活跃生长培养物中自然形成的利福平耐药菌中并未表现出来。我们可以在其他人以及我们之前的实验室/临床 菌株、 和其他细菌在 培养物、感染的巨噬细胞/动物以及肺结核患者中的抗生素暴露数据中检测到这种抗生素耐药菌的突然增加。然而，在所有这些研究中都没有注意到或报道过这种情况。这种发生在不同抗生素存活的不同细菌中的现象揭示了本研究的广泛意义。我们推测，在不同细菌感染的患者中出现的抗生素耐药性细菌克隆可能正在使用相同的机制，在持续存在抗生素的情况下快速建立抗生素耐药性种群。对抗生素具有耐受性并在持续存在抗生素的情况下存活的细菌病原体有机会获得针对抗生素的遗传抗性突变，并作为抗生素耐药菌出现。一旦抗生素耐药克隆出现，通常会牺牲生长特性，为了保护物种，在持续存在抗生素的情况下，迅速建立抗生素耐药种群非常重要。在这方面，本研究揭示了多核化和多隔膜化，随后是多次收缩，这是细菌用于快速增殖以建立抗生素耐药种群的细胞过程。该研究还指出，在我们实验室和其他实验室研究的其他细菌系统中也存在同样的现象。鉴定这些涉及快速增殖的特定细胞事件提供了其他可以与现有抗生素靶点结合的细胞过程，以预防抗生素耐药性细菌株的出现。
