Proton Motive Force Disruptors Block Bacterial Competence and Horizontal Gene Transfer
Proton Motive Force Disruptors Block Bacterial Competence and Horizontal Gene Transfer
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DOI：
10.1016/j.chom.2020.02.002
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发表时间：
2020-04-08
影响因子：
30.3
通讯作者：
Veening, Jan-Willem
中科院分区：
文献类型：
--
作者：
Domenech, Arnau;Brochado, Ana Rita;Veening, Jan-Willem
肺炎链球菌是人类鼻咽部的一种共生菌，也可引起严重的抗生素耐药感染。抗生素通过诱导肺炎链球菌的能力来驱动耐药性的传播，在这种能力中，细菌表达促进外源DNA吸收和水平基因转移（HGT）的转化机制。我们进行了高通量筛选，并确定了肺炎链球菌能力的有效抑制剂，称为com -阻滞剂。com阻滞剂通过抑制质子动力（PMF）来限制能力，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干扰物和pH稳态的改变同样会抑制能力。com阻滞剂限制临床多药耐药菌株和HGT在感染小鼠中的转化。在其有效浓度下，com阻滞剂不影响生长，损害抗生素活性，或引起可检测的耐药性。com -阻滞剂提供了一种实验工具来抑制能力和其他与pmf有关的过程，并有助于减少细菌中毒力因子的传播和抗生素耐药性。
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 multidrug-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.