Lee Ka Kiu, Łapińska Urszula, Tolle Giulia, Micaletto Maureen, Zhang Bing, Phetsang Wanida, Verderosa Anthony D, Invergo Brandon M, Westley Joseph, Bebes Attila, Yuecel Raif, O'Neill Paul A, Farbos Audrey, Jeffries Aaron R, van Houte Stineke, Caboni Pierluigi, Blaskovich Mark A T, Housden Benjamin E, Tsaneva-Atanasova Krasimira, Pagliara Stefano
Living Systems Institute, University of Exeter, Exeter, United Kingdom.
Biosciences, University of Exeter, Exeter, United Kingdom.
Elife. 2025 Jul 3;13:RP99752. doi: 10.7554/eLife.99752.
Antimicrobial resistance threatens the viability of modern medical interventions. There is a dire need to develop novel approaches to counter resistance mechanisms employed by starved or slow-growing pathogens that are refractory to conventional antimicrobial therapies. Antimicrobial peptides have been advocated as potential therapeutic solutions due to the low levels of genetic resistance observed in bacteria against these compounds. However, here we show that subpopulations of stationary phase and survive tachyplesin treatment without acquiring genetic mutations. These phenotypic variants display enhanced efflux activity to limit intracellular peptide accumulation. Differential regulation of genes involved in outer membrane vesicle secretion, membrane modification, and protease activity was also observed between phenotypically resistant and susceptible cells. We discovered that the formation of these phenotypic variants could be prevented by administering tachyplesin in combination with sertraline, a clinically used antidepressant, suggesting a novel approach for combatting antimicrobial-refractory stationary phase bacteria.
抗菌药物耐药性威胁着现代医学干预措施的有效性。迫切需要开发新方法来对抗饥饿或生长缓慢的病原体所采用的耐药机制，这些病原体对传统抗菌疗法具有抗性。抗菌肽由于在细菌中观察到的对这些化合物的低水平遗传耐药性而被倡导为潜在的治疗解决方案。然而，我们在此表明，静止期亚群在接受鲎素治疗后存活下来，且未发生基因突变。这些表型变异体表现出增强的外排活性，以限制细胞内肽的积累。在表型抗性和敏感细胞之间还观察到参与外膜囊泡分泌、膜修饰和蛋白酶活性的基因的差异调节。我们发现，将鲎素与临床使用的抗抑郁药舍曲林联合使用可以预防这些表型变异体的形成，这为对抗抗菌难治性静止期细菌提供了一种新方法。
