Mobile colistin resistance enzyme MCR-3 is a phosphoethanolamine transferase modifying lipid A in Gram-negative bacteria. MCR-3 generally mediates low-level (≤8 mg L⁻¹) colistin resistance among Enterobacteriaceae, but occasionally confers high-level (>128 mg L⁻¹) resistance in aeromonads. Herein, it is determined that MCR-3, together with another lipid A modification mediated by the arnBCADTEF operon, may be responsible for high-level colistin resistance in aeromonads. Lipid A is the critical site of pathogens for Toll-like receptor 4 recognizing. However, it is unknown whether or how MCR-3-mediated lipid A modification affects the host immune response. Compared with the wild-type strains, increased mortality is observed in mice intraperitoneally-infected with mcr-3-positive Aeromonas salmonicida and Escherichia coli strains, along with sepsis symptoms. Further, mcr-3-positive strains show decreased clearance rates than wild-type strains, leading to bacterial accumulation in organs. The increased mortality is tightly associated with the increased tissue hypoxia, injury, and post-inflammation. MCR-3 expression also impairs phagocytosis efficiency both in vivo and in vitro, contributing to the increased persistence of mcr-3-positive bacteria in tissues compared with parental strains. This study, for the first time, reveals a dual function of MCR-3 in bacterial resistance and pathogenicity, which calls for caution in treating the infections caused by mcr-positive pathogens.

中文翻译：

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移动粘菌素抗性酶 MCR-3 促进细菌逃避宿主吞噬作用

移动粘菌素抗性酶 MCR-3 是一种磷酸乙醇胺转移酶，可修饰革兰氏阴性菌中的脂质 A。MCR-3 通常介导肠杆菌科细菌的低水平（≤8 mg L ^-1）粘菌素耐药性，但偶尔会在气单胞菌中介导高水平（>128 mg L ^-1）粘菌素耐药性。在此，确定MCR-3与arnBCADTEF操纵子介导的另一种脂质A修饰一起可能是气单胞菌中高水平粘菌素抗性的原因。脂质A是Toll样受体4识别病原体的关键位点。然而，尚不清楚 MCR-3 介导的脂质 A 修饰是否或如何影响宿主免疫反应。与野生型菌株相比，在腹膜内感染mcr-3阳性杀鲑气单胞菌和大肠杆菌菌株的小鼠中观察到死亡率增加，并伴有败血症症状。此外，mcr-3阳性菌株显示出比野生型菌株降低的清除率，导致细菌在器官中积聚。死亡率的增加与组织缺氧、损伤和炎症后的增加密切相关。MCR-3 表达还会损害体内和体外的吞噬效率，与亲本菌株相比，导致组织中mcr-3阳性细菌的持久性增加。该研究首次揭示了MCR-3在细菌耐药性和致病性方面的双重功能，提示在治疗mcr阳性病原体引起的感染时需谨慎。