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 Bla_Mab 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 Bla_Mab inhibitor as part of the treatment regimen for Mab infection. These have prompted the development of potential NDM-1 and Bla_Mab 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 Bla_Mab 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 Bla_Mab 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.

Date of Award	Feb 2023
Original language	English
Supervisor	Dan Rathbone (Supervisor) & Tony Worthington (Supervisor)