Polymyxins are the last line of defense against lethal infections caused by multidrug resistant Gram-negative pathogens.Very recently, the use of polymyxins has been greatly challenged by the emergence of the plasmid-bome mobile colistin resistance gene (mcr-1).However, the mechanistic aspects of the MCR-1 colistin resistance are still poorly understood.Here we report the comparative genomics of two new mcr-1-harbouring plasmids isolated from the human gut microbiota, highlighting the diversity in plasmid transfer of the mcr1 gene.Further genetic dissection delineated that both the trans-membrane region and a substrate-binding motif are required for the MCR-1-mediated colistin resistance.The soluble form of the membrane protein MCR-1 was successfully prepared and verified.Phylogenetic analyses revealed that MCR-1 is highly homologous to its counterpart PEA lipid A transferase in Paenibacili, a known producer of polymyxins.The fact that the plasmid-bome MCR-1 is placed in a subclade neighboring the chromosome-encoded colistin-resistant Neisseria LptA (EptA) potentially implies parallel evolutionary paths for the two genes.In conclusion,our finding provids a first glimpse of mechanism for the MCR-1-mediated colistin resistance.
Rongsui Gao Yongfei Hu Zhencui Li Jian Sun Qingjing Wang Jingxia Lin Huiyan Ye Fei Liu Swaminath Srinivas Defeng Li Baoli Zhu Ya-Hong Liu Guo-Bao Tian Youjun Feng
Department of Medical Microbiology and Parasitology, Zhejiang University School of Medicine, Hangzho CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Aca National Risk Assessment Laboratory for Antimicrobial Resistance of Animal Original Bacteria, South Department of Biochemistry, University of Illinois, Urbana, Illinois, United States of America Institute of Biophysics, Chinese Academy of Sciences, Beijing, China Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China