Synthesis and Biological Characterisation of Potential Inhibitors of Microbial β-Lactamases

Abstract

Antibiotic resistance remains a global health challenge and arguably, could be described as a silent pandemic. Bacterial β-lactamases are among the major promoters of antibiotic resistance owing to their virulence against the most commonly used class of antibiotics. β-Lactamases such as NDM-1 and BlaMab are broad-spectrum, antibiotic-degrading enzymes that are associated with life-threatening infections. The therapeutic relevance of β-lactam antibiotics remains obscure considering the absence of clinically significant NDM-1 inhibitor(s) while the cure rate of Mycobacterium abscessus (Mab) infection in patients with cystic fibrosis remains low due to the lack of BlaMab inhibitor as part of the treatment regimen for Mab infection. These have prompted the development of potential NDM-1 and BlaMab inhibitors respectively. Potential bis cyclo-oxamide prodrugs/α,β-unsaturated carbonyl compounds and bicyclic/tricyclic N,S- acetals were successfully synthesised and characterised as potential inhibitors of NDM-1 and BlaMab enzymes respectively. Potential NDM-1 polar and hydrophobic interactions with the respective bis cyclo-oxamide and the unsaturated carbonyl compounds were identified by crystallographic studies while TLC-based inhibitory screening of the bis cyclo-oxamide prodrugs showed some of the compounds functioned as NDM-1 inhibitors, rather than a prodrug that was expected to release oxalate anion in the presence of NDM-1, at a concentration of ≥1.78 mM. However, a rapid nitrocefin test identified oxalate anion as a potential inhibitor of NDM-1. The synthesised bicyclic and tricyclic N,S-acetals are analogues of a potent BlaMab inhibitor (lead compound). The bioisosteric modification of the lead compound resulted in the loss of inhibitory activity but two of these analogues displayed limited antimicrobial activity against some Gram-negative bacteria. The study demonstrates that the bis cyclo-oxamides are potential inhibitors of NDM-1 and the enzyme is also sensitive to oxalate anion, hence, the anion can be employed as an active drug agent in the development of NDM-1 prodrugs.