Quorum sensing plays an important role in heteroresistance regulation of Pseudomonas aeruginosa

Abstract Background: The prevalence and genetic mechanism of antibiotic heteroresistance attracted more and more research attentions. However, its non-genenic mechanism is still largely unknown. As the most important mechanism that enable individual bacteria to coordinate their behavior in populations, the influence of Quorum sensing (QS) on heteroresistance was disclosed here. Results: We investigated the prevalence of heteroresistance in 170 clinical isolates of P. aeruginosa against 7 different antibiotics. The population analysis profiles showed that P. aeruginosa was frequently heteroresistant to meropenem (MEM), amikacin (AMK), ciprofloxacin (CIP) and Ceftazidime (CAZ), which was related to down-regulated expression of QS genes lasI and rhlI. Further loss-of-function studies revealed that deficiency of lasI/rhlI facilitated heteroresistance of P. aeruginosa to all the above four antibiotics, which was abrogated by overexpression of lasI/rhlI or treatment with 3-oxo-C12-HSL/C4-HSL. In addition, we found that the expression of oprD and efflux-associated genes was regulated by lasI/rhlI, while downregulation of oprD and upregulation of efflux-associated genes was observed in heteroresistant subpopulation. Conclusions: These data suggest that QS plays a crucial role in heteroresistance regulation, partially mediated by oprD and efflux-associated genes. Our findings highlight the new function of QS and provide new insight into the mechanism of heteroresistance in the context of non-genetic factor.