Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, College of Veterinary Medicine, Yangzhou University, Yangzhou, China.
Joint International Research Laboratory of Agriculture and Agri-Product Safety, the Ministry of Education of China, Yangzhou University, Yangzhou, China.
Antimicrob Agents Chemother. 2024 Apr 3;68(4):e0126123. doi: 10.1128/aac.01261-23. Epub 2024 Feb 28.
Antibiotic resistance represents a significant challenge to public health and human safety. The primary driver behind the dissemination of antibiotic resistance is the horizontal transfer of plasmids. Current conjugative transfer assay is generally performed in a standardized manner, ignoring the effect of the host environment. Host defense peptides (HDPs) possess a wide range of biological targets and play an essential role in the innate immune system. Herein, we reveal that sub-minimum inhibitory concentrations of HDPs facilitate the conjugative transfer of RP4-7 plasmid in the Luria Broth medium, and this observation is reversed in the RPMI medium, designed to simulate the host environment. Out of these HDPs, indolicidin (Ind), a cationic tridecapeptide from bovine neutrophils, significantly inhibits the conjugation of multidrug resistance plasmids in a dose-dependent manner, including - and (X4)-bearing plasmids. We demonstrate that the addition of Ind to RPMI medium as the incubation substrate downregulates the expression of conjugation-related genes. In addition, Ind weakens the tricarboxylic acid cycle, impedes the electron transport chain, and disrupts the proton motive force, consequently diminishing the synthesis of adenosine triphosphate and limiting the energy supply. Our findings highlight the importance of the host-like environments for the development of horizontal transfer inhibitors and demonstrate the potential of HDPs in preventing the spread of resistance plasmids.
抗生素耐药性对公共卫生和人类安全构成重大挑战。抗生素耐药性传播的主要驱动力是质粒的水平转移。目前的共轭转移测定通常以标准化的方式进行，忽略了宿主环境的影响。宿主防御肽 (HDP) 具有广泛的生物学靶标，在先天免疫系统中发挥着重要作用。在这里，我们揭示了低于最低抑菌浓度的 HDP 促进了 Luria Broth 培养基中 RP4-7 质粒的共轭转移，而在模拟宿主环境的 RPMI 培养基中则出现了逆转。在这些 HDP 中，Indolicidin (Ind)，一种来自牛中性粒细胞的阳离子十三肽，以剂量依赖的方式显著抑制多药耐药质粒的共轭，包括 - 和 (X4) 携带的质粒。我们证明，将 Ind 添加到 RPMI 培养基中作为孵育底物可下调与共轭相关的基因表达。此外，Ind 削弱三羧酸循环，阻碍电子传递链，并破坏质子动力势，从而减少三磷酸腺苷的合成并限制能量供应。我们的研究结果强调了宿主样环境对于开发水平转移抑制剂的重要性，并展示了 HDP 在防止耐药质粒传播方面的潜力。
