Polymyxin resistance caused by large-scale genomic inversion due to IS<i>26</i> intramolecular translocation in <i>Klebsiella pneumoniae</i>.

Haibin LI; Lang Sun; Han Qiao; Zongti Sun; Penghe Wang; Chunyang Xie; Xinxin HU; Tongying Nie; Xinyi Yang; Guoqing LI; Youwen Zhang; Xiukun Wang; Zhuorong LI; Jiandong Jiang; Congran LI; Xuefu You

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Polymyxin resistance caused by large-scale genomic inversion due to IS26 intramolecular translocation in Klebsiella pneumoniae.

Author: Haibin LI ¹ ; Lang SUN ¹ ; Han QIAO ¹ ; Zongti SUN ¹ ; Penghe WANG ¹ ; Chunyang XIE ¹ ; Xinxin HU ¹ ; Tongying NIE ¹ ; Xinyi YANG ¹ ; Guoqing LI ¹ ; Youwen ZHANG ¹ ; Xiukun WANG ¹ ; Zhuorong LI ² ; Jiandong JIANG ¹ ; Congran LI ¹ ; Xuefu YOU ¹
Author Information

1. Beijing Key Laboratory of Antimicrobial Agents, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China.
2. Institute of Medicinal Biotechnology, Chinese Academy of Medical Science & Peking Union Medical College, Beijing 100050, China.
Publication Type:Journal Article
Keywords: IS26; Inversion; Klebsiella pneumoniae; Polymyxin resistance; Structural variation; Whole genome sequencing; mgrB
From: Acta Pharmaceutica Sinica B 2023;13(9):3678-3693
CountryChina
Language:English
Abstract: Polymyxin B and polymyxin E (colistin) are presently considered the last line of defense against human infections caused by multidrug-resistant Gram-negative organisms such as carbapenemase-producer Enterobacterales, Acinetobacter baumannii, and Klebsiella pneumoniae. Yet resistance to this last-line drugs is a major public health threat and is rapidly increasing. Polymyxin S₂ (S₂) is a polymyxin B analogue previously synthesized in our institute with obviously high antibacterial activity and lower toxicity than polymyxin B and colistin. To predict the possible resistant mechanism of S₂ for wide clinical application, we experimentally induced bacterial resistant mutants and studied the preliminary resistance mechanisms. Mut-S, a resistant mutant of K. pneumoniae ATCC BAA-2146 (Kpn2146) induced by S₂, was analyzed by whole genome sequencing, transcriptomics, mass spectrometry and complementation experiment. Surprisingly, large-scale genomic inversion (LSGI) of approximately 1.1 Mbp in the chromosome caused by IS26 mediated intramolecular transposition was found in Mut-S, which led to mgrB truncation, lipid A modification and hence S₂ resistance. The resistance can be complemented by plasmid carrying intact mgrB. The same mechanism was also found in polymyxin B and colistin induced drug-resistant mutants of Kpn2146 (Mut-B and Mut-E, respectively). This is the first report of polymyxin resistance caused by IS26 intramolecular transposition mediated mgrB truncation in chromosome in K. pneumoniae. The findings broaden our scope of knowledge for polymyxin resistance and enriched our understanding of how bacteria can manage to survive in the presence of antibiotics.