期刊
ACTA PHARMACEUTICA SINICA B
卷 13, 期 9, 页码 3678-3693出版社
INST MATERIA MEDICA, CHINESE ACAD MEDICAL SCIENCES
DOI: 10.1016/j.apsb.2023.06.003
关键词
Polymyxin resistance; Whole genome; Structural variation; Inversion; mgrB; IS26; sequencing
Polymyxin B and polymyxin E are last-line antibiotics for multidrug-resistant Gram-negative infections, but resistance is increasing. Polymyxin S2, a new analogue, shows high antibacterial activity and lower toxicity. Resistance mechanism of S2 is similar to polymyxin B and polymyxin E.
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-lin e drugs isa major public health threat and is rapidly increasing. Polymyxin S2 (S2) isa 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. Surpris-ingly, 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 modifica-tion 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
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