Authors
Shuyu Tan, Wenjuan Yin, Jian Sun, Wenguang Xiong, Yina An, Lu Qiao, Pu Zhang, Siqi Sun, Qianru Li, Leiming Fu, Yifan Liu, Yaqian Xue, Shuyi Huang, Yixi Liu, Yang Wang, Yanjun Dong
Published in
PLoS pathogens. Volume 22. Issue 7. Pages e1014427. Jul 14, 2026. Epub Jul 14, 2026.
Abstract
Mobile colistin resistance (mcr) genes compromise the efficacy of last-resort polymyxin antibiotics. Notably, the global prevalence of mcr-3 has continued to increase despite reductions in colistin use, suggesting that selective forces beyond direct antibiotic pressure contribute to its persistence. Here, mcr-3-positive Escherichia coli is shown to confer a survival advantage by reprogramming macrophage immunity. MCR-3-mediated lipid A modification blunted TLR4-NF-κB signaling, suppressed macrophage reactive oxygen species 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 and energy metabolism. 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 negative strains under antibiotic treatment without differing in in vitro susceptibility, indicating that immune evasion rather than intrinsic drug resistance alone drives their competitive advantage. These findings reveal a dual mechanism where mcr-3 confers both antimicrobial resistance and immune suppression, enabling persistence under antibiotic pressure and highlighting the threat of mcr-3 dissemination independent of polymyxin use.
PMID:
42447151
Bibliographic data and abstract were imported from PubMed on 15 Jul 2026.
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