부산대학교 도서관

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. Author summary: By influencing the physiology of bacterial pathogens, the host environment can either limit or potentiate the effectiveness of antibiotics during infection. Recently, we demonstrated that host reactive nitrogen species (RNS), generated by macrophages in response to Salmonella infection, can transiently shield a subset of recalcitrant cells from the effects of β-lactam antibiotics by reducing their cellular respiration. Here, we showed that although bacteria intoxicated by RNS are protected from β-lactam antibiotics, they remain highly susceptible to fluoroquinolones, another class of antibiotics. We found that by reducing cellular respiration, host RNS collaterally inactivate bacterial efflux machinery, which is an essential determinant of fluoroquinolone recalcitrance. Our study explains how the modulation of bacterial respiration by the host environment can differentially impact antibiotic effectiveness during infection. Understanding how host factors influence the physiology of pathogens is essential for optimizing antibiotic use. [ABSTRACT FROM AUTHOR]