期刊
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
卷 65, 期 4, 页码 -出版社
AMER SOC MICROBIOLOGY
DOI: 10.1128/AAC.01714-20
关键词
IMP; S262G; V67F; beta-lactamase; carbapenemase; carbapenems; imipenemase
资金
- National Institutes of Health [GM111926, R35 GM128595, R15 GM134454]
- Robert A. Welch Foundation [F-1572]
- National Institute of Allergy and Infectious Diseases of the National Institutes of Health (NIH) [R01AI100560, R01AI063517, R01AI072219]
- Cleveland Department of Veterans Affairs from the Biomedical Laboratory Research & Development Service of the VA Office of Research and Development [1I01BX001974]
- Geriatric Research Education and Clinical Center [VISN 10]
Metallo-beta-lactamases (MBLs) are a growing clinical threat as they inactivate most beta-lactam antibiotics. Variants of the IMP-1 gene exhibit increased resistance to carbapenems but do not confer additional survival advantage in limited zinc availability. Evolution of MBL subfamilies like IMP-6, -10, and -78 appears to be driven by different selective pressures.
Metallo-beta-lactamases (MBLs) are a growing clinical threat because they inactivate nearly all beta-lactam-containing antibiotics, and there are no clinically available inhibitors. A significant number of variants have already emerged for each MBL subfamily. To understand the evolution of imipenemase (IMP) genes (bla(IMP)) and their clinical impact, 20 clinically derived IMP-1 like variants were obtained using site-directed mutagenesis and expressed in a uniform genetic background in Escherichia coli strain DH10B. Strains of IMP-1-like variants harboring S262G or V67F substitutions exhibited increased resistance toward carbapenems and decreased resistance toward ampicillin. Strains expressing IMP-78 (S262G/V67F) exhibited the largest changes in MIC values compared to IMP-1. In order to understand the molecular mechanisms of increased resistance, biochemical, biophysical, and molecular modeling studies were conducted to compare IMP-1, IMP-6 (S262G), IMP-10 (V67F), and IMP-78 (S262G/V67F). Finally, unlike most New Delhi metallo-beta-lactamase (NDM) and Verona integron-encoded metallo-beta-lactamase (VIM) variants, the IMP-1-like variants do not confer any additional survival advantage if zinc availability is limited. Therefore, the evolution of MBL subfamilies (i.e., IMP-6, -10, and -78) appears to be driven by different selective pressures.
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