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
Abstract
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.