Biology Department, Boston College, Chestnut Hill, MA, 02467, USA.
Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.
Nat Commun. 2022 Jun 7;13(1):3165. doi: 10.1038/s41467-022-30967-4.
Detailed knowledge on how bacteria evade antibiotics and eventually develop resistance could open avenues for novel therapeutics and diagnostics. It is thereby key to develop a comprehensive genome-wide understanding of how bacteria process antibiotic stress, and how modulation of the involved processes affects their ability to overcome said stress. Here we undertake a comprehensive genetic analysis of how the human pathogen Streptococcus pneumoniae responds to 20 antibiotics. We build a genome-wide atlas of drug susceptibility determinants and generated a genetic interaction network that connects cellular processes and genes of unknown function, which we show can be used as therapeutic targets. Pathway analysis reveals a genome-wide atlas of cellular processes that can make a bacterium less susceptible, and often tolerant, in an antibiotic specific manner. Importantly, modulation of these processes confers fitness benefits during active infections under antibiotic selection. Moreover, screening of sequenced clinical isolates demonstrates that mutations in genes that decrease antibiotic sensitivity and increase tolerance readily evolve and are frequently associated with resistant strains, indicating such mutations could be harbingers for the emergence of antibiotic resistance.
详细了解细菌如何逃避抗生素并最终产生耐药性，可以为新型治疗方法和诊断方法开辟途径。因此，关键是要全面了解细菌如何处理抗生素压力，以及调节相关过程如何影响其克服这种压力的能力。在这里，我们对人类病原体肺炎链球菌如何对 20 种抗生素做出反应进行了全面的遗传分析。我们构建了一个药物敏感性决定因素的全基因组图谱，并生成了一个遗传相互作用网络，该网络连接了细胞过程和功能未知的基因，我们证明这些基因可以作为治疗靶点。通路分析揭示了一个可以使细菌在抗生素特异性方式下降低敏感性且通常具有耐受性的全基因组细胞过程图谱。重要的是，在抗生素选择下的活性感染中，这些过程的调节赋予了适应性优势。此外，对测序临床分离株的筛选表明，降低抗生素敏感性和增加耐受性的基因的突变很容易进化，并且经常与耐药株相关，这表明这些突变可能是抗生素耐药性出现的先兆。
