Department of Molecular Microbiology and Immunology, Brown University, Providence, Rhode Island, USA.
Department of Orthopedics, Warren Alpert Medical School of Brown University, Providence, Rhode Island, USA.
Antimicrob Agents Chemother. 2021 Sep 17;65(10):e0089121. doi: 10.1128/AAC.00891-21. Epub 2021 Aug 2.
Mutagenesis is integral for bacterial evolution and the development of antibiotic resistance. Environmental toxins and stressors are known to elevate the rate of mutagenesis through direct DNA toxicity, known as stress-associated mutagenesis, or via a more general stress-induced process that relies on intrinsic bacterial pathways. Here, we characterize the spectra of mutations induced by an array of different stressors using high-throughput sequencing to profile thousands of spectinomycin-resistant colonies of Bacillus subtilis. We found 69 unique mutations in the and genes, and that each stressor leads to a unique and specific spectrum of antibiotic-resistance mutations. While some mutations clearly reflected the DNA damage mechanism of the stress, others were likely the result of a more general stress-induced mechanism. To determine the relative fitness of these mutants under a range of antibiotic selection pressures, we used multistrain competitive fitness experiments and found an additional landscape of fitness and resistance. The data presented here support the idea that the environment in which the selection is applied (mutagenic stressors that are present), as well as changes in local drug concentration, can significantly alter the path to spectinomycin resistance in B. subtilis.
突变是细菌进化和抗生素耐药性发展的必要条件。已知环境毒素和应激源通过直接的 DNA 毒性（称为应激相关突变）或通过依赖于固有细菌途径的更普遍的应激诱导过程来提高突变率。在这里，我们使用高通量测序来描述枯草芽孢杆菌数千个壮观霉素抗性菌落，以鉴定多种应激源诱导的突变谱。我们在和基因中发现了 69 个独特的突变，并且每个应激源都导致独特且特定的抗生素耐药性突变谱。虽然一些突变明显反映了应激的 DNA 损伤机制，但其他突变可能是更普遍的应激诱导机制的结果。为了确定这些突变体在一系列抗生素选择压力下的相对适应性，我们使用多菌株竞争适应性实验发现了适应性和耐药性的另一个景观。这里呈现的数据支持这样一种观点，即选择施加的环境（存在的诱变应激源）以及局部药物浓度的变化，可以显著改变枯草芽孢杆菌壮观霉素耐药的途径。
