Project description:<p>Mobile colistin resistance (mcr) genes undermine the efficacy of last-line polymyxin antibiotics, and the global prevalence of mcr-3 continues to rise despite reduced colistin use. Here, we show that mcr-3-positive Escherichia coli (E. coli) confers a survival advantage by reprogramming macrophage immunity. MCR-3-mediated lipid A modification blunted TLR4-NF-kappaB signaling, suppressed macrophage reactive oxygen species (ROS) generation, and delayed phagosome-lysosome fusion, allowing mcr-3-positive strains to evade intracellular killing. Integrated transcriptomic and metabolomic analyses revealed extensive immunometabolic rewiring in infected macrophages, including altered glycerophospholipid metabolism and iron homeostasis. Consistently, mcr-3 enhanced bacterial tolerance to ferrous iron stress, likely mitigating host-induced ferroptotic damage. In a mouse co-infection model, mcr-3-positive strains outcompeted isogenic mcr-3-negative strains under antibiotic treatment without any difference in antibiotic susceptibility in vitro. These findings reveal a dual-action mechanism that mcr-3 endows E. coli with both antibiotic resistance and host immune suppression, enabling persistence under antibiotic pressure and highlighting the long-term threat of mcr-3 dissemination even in the absence of polymyxin use.</p>
Project description:This experiment was designed to find differences and similarities between the loss-of-AcrB-efflux-function mutants of two Enterobacterales, in stationary phase. Cultures were grown in LB broth for 10 hours. Four biological replicates per strain were analysed.
