Molecular Genetics Group, Groningen Biomolecular Sciences and Biotechnology Institute, Centre for Synthetic Biology, University of Groningen, Groningen 9747AG, the Netherlands; Department of Fundamental Microbiology, Faculty of Biology and Medicine, University of Lausanne, Biophore Building, Lausanne 1015, Switzerland.
European Molecular Biology Laboratory, Genome Biology Unit, Heidelberg 69117, Germany.
Cell Host Microbe. 2020 Apr 8;27(4):544-555.e3. doi: 10.1016/j.chom.2020.02.002. Epub 2020 Mar 3.
Streptococcus pneumoniae is a commensal of the human nasopharynx that can also cause severe antibiotic-resistant infections. Antibiotics drive the spread of resistance by inducing S. pneumoniae competence, in which bacteria express the transformation machinery that facilitates uptake of exogenous DNA and horizontal gene transfer (HGT). We performed a high-throughput screen and identified potent inhibitors of S. pneumoniae competence, called COM-blockers. COM-blockers limit competence by inhibiting the proton motive force (PMF), thereby disrupting export of a quorum-sensing peptide that regulates the transformation machinery. Known chemical PMF disruptors and alterations in pH homeostasis similarly inhibit competence. COM-blockers limit transformation of clinical multi-drug-resistant strains and HGT in infected mice. At their active concentrations, COM-blockers do not affect growth, compromise antibiotic activity, or elicit detectable resistance. COM-blockers provide an experimental tool to inhibit competence and other PMF-involved processes and could help reduce the spread of virulence factors and antibiotic resistance in bacteria. VIDEO ABSTRACT.
肺炎链球菌是人类鼻咽部的共生菌，也可导致严重的抗生素耐药感染。抗生素通过诱导肺炎链球菌感受态，促进耐药性的传播，在感受态中，细菌表达转化机制，促进外源 DNA 的摄取和水平基因转移（HGT）。我们进行了高通量筛选，鉴定出了强效的肺炎链球菌感受态抑制剂，称为 COM 阻断剂。COM 阻断剂通过抑制质子动力势（PMF）来限制感受态，从而破坏调节转化机制的群体感应肽的输出。已知的化学 PMF 破坏剂和 pH 稳态的改变也能抑制感受态。COM 阻断剂限制了临床多药耐药株的转化和感染小鼠中的 HGT。在其有效浓度下，COM 阻断剂不会影响生长、降低抗生素活性或引起可检测的耐药性。COM 阻断剂为抑制感受态和其他涉及 PMF 的过程提供了一个实验工具，有助于减少细菌中毒力因子和抗生素耐药性的传播。视频摘要。
