Structure Guided Discovery of Novel Pan Metallo-β-Lactamase Inhibitors with Improved Gram-Negative Bacterial Cell Penetration

The use of β-lactam (BL) and
β-lactamase
inhibitor
combination to overcome BL antibiotic resistance has been validated
through clinically approved drug products. However, unmet medical
needs still exist for the treatment of infections caused by Gram-negative
(GN) bacteria expressing metallo-β-lactamases. Previously, we
reported our effort to discover pan inhibitors of three main families
in this class: IMP, VIM, and NDM. Herein, we describe our work to
improve the GN coverage spectrum in combination with imipenem and
relebactam. This was achieved through structure- and property-based
optimization to tackle the GN cell penetration and efflux challenges.
A significant discovery was made that inhibition of both VIM alleles,
VIM-1 and VIM-2, is essential for broad GN coverage, especially against
VIM-producing P. aeruginosa. In addition, pharmacokinetics
and nonclinical safety profiles were investigated for select compounds.
Key findings from this drug discovery campaign laid the foundation
for further lead optimization toward identification of preclinical
candidates.