Department of Chemistry and Molecular Biology, University of Gothenburg, Gothenburg, Sweden.
Centre for Antibiotic Resistance Research (CARe), University of Gothenburg, Gothenburg, Sweden.
Drug Dev Res. 2019 Feb;80(1):19-23. doi: 10.1002/ddr.21457. Epub 2018 Oct 21.
Antibiotic resistance, especially in gram-negative bacteria, is spreading globally and rapidly. Development of new antibiotics lags behind; therefore, novel approaches to the problem of antibiotic resistance are sorely needed and this commentary highlights one relatively unexplored target for drug development: conjugation. Conjugation is a common mechanism of horizontal gene transfer in bacteria that is instrumental in the spread of antibiotic resistance among bacteria. Most resistance genes are found on mobile genetic elements and primarily spread by conjugation. Furthermore, conjugative elements can act as a reservoir to maintain antibiotic resistance in the bacterial population even in the absence of antibiotic selection. Thus, conjugation can spread antibiotic resistance quickly between bacteria of the microbiome and pathogens when selective pressure (antibiotics) is introduced. Potential drug targets include the plasmid-encoded conjugation system and the host-encoded proteins important for conjugation. Ideally, a conjugation inhibitor will be used alongside antibiotics to prevent the spread of resistance to or within pathogens while not acting as a growth inhibitor itself. Inhibiting conjugation will be an important addition to our arsenal of strategies to combat the antibiotic resistance crisis, allowing us to extend the usefulness of antibiotics.
抗生素耐药性，特别是革兰氏阴性菌的耐药性，正在全球范围内迅速蔓延。新抗生素的研发滞后；因此，非常需要寻找解决抗生素耐药性问题的新方法，本评论强调了一个相对未被探索的药物研发目标： conjugation（细菌接合）。 conjugation 是细菌中水平基因转移的常见机制，在细菌之间抗生素耐药性的传播中起着重要作用。大多数耐药基因位于可移动的遗传元件上，主要通过 conjugation 传播。此外，conjugative elements 可以作为储库，在没有抗生素选择的情况下维持细菌群体中的抗生素耐药性。因此，当选择性压力（抗生素）引入时， conjugation 可以在微生物组中的细菌和病原体之间快速传播抗生素耐药性。潜在的药物靶点包括质粒编码的 conjugation 系统和宿主编码的 conjugation 相关蛋白。理想情况下，conjugation 抑制剂将与抗生素一起使用，以防止耐药性在病原体之间或内部传播，而本身不会作为生长抑制剂。抑制 conjugation 将是我们对抗抗生素耐药性危机的策略库中的一个重要补充，使我们能够延长抗生素的使用效果。
