摘要

压力诱导诱变可以帮助病原体在抗生素治疗期间产生耐药细胞;然而，如果和如何抗生素诱导微生物诱变仍然知之甚少。非致病嗜热菌，嗜热地芽孢杆菌HTA426，分别通过rpoB和rpsL突变有效地产生对利福平和链霉素有抗性的衍生细胞。在这里，我们检查了这种现象，提出了一种由抗生素诱导的新型致突变模式。波动分析表明突变发生在文化过程中的自发突变。然而，生长细胞中的突变比固定细胞更频繁，并且突变位点通过细胞生长而变化。这些观察结果表明生长细胞响应抗生素诱导了诱变。 mfd的框内缺失，控制转录偶联修复以纠正转录链上的DNA损伤，导致生长和固定细胞之间相当的突变;因此，诱变机制可归因于生长细胞抑制mfd功能的DNA修复缺陷。 G.kaustophilus的最佳生长温度下发生的突变比在更高的生长温度下更频繁地发生，表明诱变依赖活性细胞活性而不是高温相关的DNA损伤。另外，除了mfd抑制之外，诱变可能涉及靶向这些位点的诱变因子，因为在转录链上的胸腺嘧啶和鸟嘌呤位点rpoB和rpsL突变占优势。对于其他土芽孢杆菌属和嗜热芽孢杆菌菌种观察到相似的致突变特征。这表明芽孢杆菌相关嗜热菌通常诱导对利福平和链霉素产生抗性细胞的诱变。

Stress-induced mutagenesis can assist pathogens in generating drug-resistant cells during antibiotic therapy; however, if and how antibiotics induce mutagenesis in microbes remains poorly understood. A non-pathogenic thermophile, Geobacillus kaustophilus HTA426, efficiently produces derivative cells resistant to rifampicin and streptomycin viarpoB and rpsL mutations, respectively. Here, we examined this phenomenon to suggest a novel mutagenic mode induced by antibiotics. Fluctuation analysis indicated that mutations occurred via spontaneous mutations during culture. However, mutations were much more frequent in growing cells than stationary cells, and mutation sites were varied through cell growth. These observations suggested that growing cells induced mutagenesis in response to antibiotics. An in-frame deletion of mfd, which governs transcription-coupled repair to correct DNA lesions on the transcribed strand, caused mutations that were comparable between growing and stationary cells; therefore, the mutagenic mechanism was attributable to DNA repair defects where growing cells depressed mfd function. Mutations occurred more frequently at optimal growth temperatures for G. kaustophilus than at a higher growth temperature, suggesting that the mutagenesis relies on active cellular activities rather than high temperature-associated DNA damage. In addition, the mutagenesis may involve a mutagenic factor targeting these sites, in addition to mfd depression, because rpoB andrpsL mutations were dominant at thymine and guanine sites on the transcribed strand. A similar mutagenic profile was observed for otherGeobacillus and thermophilic Bacillus species. This suggests thatBacillus-related thermophiles commonly induce mutagenesis in response to rifampicin and streptomycin to produce resistant cells.

https://www.nature.com/articles/s41429-017-0003-1