PDF(Pubmed)
Abstract：
The host environment is of critical importance for antibiotic efficacy. By impacting bacterial machineries, stresses encountered by pathogens during infection promote the formation of phenotypic variants that are transiently insensitive to the action of antibiotics. It is assumed that these recalcitrant bacteria-termed persisters-contribute to antibiotic treatment failure and relapsing infections. Recently, we demonstrated that host reactive nitrogen species (RNS) transiently protect persisters against the action of β-lactam antibiotics by delaying their regrowth within host cells. Here, we discovered that RNS intoxication of persisters also collaterally sensitizing them to fluoroquinolones during infection, explaining the higher efficiency of fluoroquinolones against intramacrophage Salmonella. By reducing bacterial respiration and the proton-motive force, RNS inactivate the AcrAB efflux machinery of persisters, facilitating the accumulation of fluoroquinolones intracellularly. Our work shows that target inactivity is not the sole reason for Salmonella persisters to withstand antibiotics during infection, with active efflux being a major contributor to survival. Thus, understanding how the host environment impacts persister physiology is critical to optimize antibiotics efficacy during infection.
摘要：
宿主环境对于抗生素功效至关重要。通过影响细菌机器，病原体在感染过程中遇到的压力促进了表型变体的形成，这些变体对抗生素的作用暂时不敏感。假定这些顽固性细菌-称为持久性细菌-导致抗生素治疗失败和复发性感染。最近,我们证明，宿主反应性氮物种（RNS）通过延迟其在宿主细胞内的再生长来暂时保护持久性细胞免受β-内酰胺抗生素的作用。这里,我们发现，持久性药物的RNS中毒也会使它们在感染期间对氟喹诺酮类药物敏感，解释了氟喹诺酮类药物对嗜酸性沙门氏菌的更高效率。通过减少细菌呼吸和质子动力，RNS使坚持者的AcrAB外排机制失活，促进氟喹诺酮类药物在细胞内的积累。我们的工作表明，目标不活动并不是沙门氏菌持续感染期间耐受抗生素的唯一原因，主动外排是生存的主要原因。因此，了解宿主环境如何影响持久性生理学对于优化感染期间的抗生素疗效至关重要。
