Carbapenem Use Is Driving the Evolution of Imipenemase 1 Variants

Zishuo Cheng; Christopher R Bethel; Pei W Thomas; Ben A Shurina; John-Paul Alao; Caitlyn A Thomas; Kundi Yang; Steven H Marshall; Huan Zhang; Aidan M Sturgill; Andrea N Kravats; Richard C Page; Walter Fast; Robert A Bonomo; Michael W Crowder

doi:10.1128/AAC.01714-20

Carbapenem Use Is Driving the Evolution of Imipenemase 1 Variants

Antimicrob Agents Chemother. 2021 Mar 18;65(4):e01714-20. doi: 10.1128/AAC.01714-20. Print 2021 Mar 18.

Authors

Zishuo Cheng¹, Christopher R Bethel², Pei W Thomas³, Ben A Shurina¹, John-Paul Alao¹, Caitlyn A Thomas¹, Kundi Yang¹, Steven H Marshall², Huan Zhang¹, Aidan M Sturgill¹, Andrea N Kravats⁴, Richard C Page¹, Walter Fast³, Robert A Bonomo^{5

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12}, Michael W Crowder⁴

Affiliations

¹ Department of Chemistry and Biochemistry, Miami University, Oxford, Ohio, USA.
² Research Services, Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Cleveland, Ohio, USA.
³ Division of Chemical Biology and Medicinal Chemistry, College of Pharmacy, and the LaMontagne Center for Infectious Disease, University of Texas, Austin, Texas, USA.
⁴ Department of Chemistry and Biochemistry, Miami University, Oxford, Ohio, USA kravatan@miamioh.edu robert.bonomo@va.gov crowdemw@miamioh.edu.
⁵ Research Services, Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Cleveland, Ohio, USA kravatan@miamioh.edu robert.bonomo@va.gov crowdemw@miamioh.edu.
⁶ Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.
⁷ Department of Pharmacology, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.
⁸ Department of Molecular Biology and Microbiology, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.
⁹ Department of Biochemistry, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.
¹⁰ Department of Proteomics and Bioinformatics, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.
¹¹ Medical Service and GRECC, Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Cleveland, Ohio, USA.
¹² CWRU-Cleveland VAMC Center for Antimicrobial Resistance and Epidemiology (CASE VA CARES), Cleveland, Ohio, USA.

Abstract

Metallo-β-lactamases (MBLs) are a growing clinical threat because they inactivate nearly all β-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-β-lactamase (NDM) and Verona integron-encoded metallo-β-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.

Keywords: IMP; S262G; V67F; beta-lactamase; carbapenemase; carbapenems; imipenemase.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Anti-Bacterial Agents / pharmacology
Anti-Bacterial Agents / therapeutic use
Carbapenems* / pharmacology
Escherichia coli / genetics
Microbial Sensitivity Tests
beta-Lactamases* / genetics

Substances

Anti-Bacterial Agents
Carbapenems
beta-Lactamases

Abstract

Publication types

MeSH terms

Substances

Grants and funding