Introduction

New Delhi metallo beta-lactamase-1 (NDM-1) is a major contributor to the global rise of antimicrobial resistance due to its ability to hydrolyse most beta-lactam antibacterial agents, including last-line carbapenems [1]. NDM-1 was first identified in 2008 in Klebsiella pneumoniae isolate from a Swedish patient previously hospitalized in India [2]. Since then, NDM-1 has emerged as a significant antimicrobial resistance mechanism [3] and has been detected in Escherichia coli, Proteae, and Acinetobacter species and other Enterobacterial species [4-7]. NDM-1 is often encoded in gene cassettes within integrons and plasmids, along with other resistance genes, thereby promoting its spread through horizontal gene transfer [8].

NDM-1 belongs to the B1 subclass within the metallo-beta-Lactamase (MBLs) and is a zinc-dependent enzyme in which catalysis is driven by a metal-activated hydroxide ion that promotes β-lactam ring hydrolysis. Consequently, NDM-1 is resistant to traditional serine lactamase inhibitors such as sulbactam, clavulanic acid and avibactam. Interestingly, monobactams are stable against MBL due to their monocyclic ring, which maintains spatial separation from the zinc ion in the active site [4,8-10].

NDM-1-producing bacterial strains exhibit resistance to a wide variety of antibacterial agents, including carbapenems, which are a last-resort therapy for multidrug-resistant bacterial infections. NDM-1 has received special focus because of its wide substrate coverage, high rate of spread through mobile genetic elements and high mortality rates associated with infections caused by NDM-1-producing bacteria. Moreover, these strains spread quickly within and across species and they have been detected in both drinking water and wastewater, highlighting the complexity of combating their spread [11-13].

The development of novel antibacterial agents that are naturally resistant to hydrolysis by NDM-1 is a complex, time-consuming, and expensive process, highlighting the importance of an alternative approach, such as restoring antibiotic potency by using inhibitors that shield β-lactams against NDM-1 hydrolysis. To date, there is no clinically approved inhibitor for NDM-1, despite extensive in silico and in vitro studies [1,4,11]. The variability in the entry loop permutation of the active site, the limited number of scaffolds capable of selectively targeting the NDM-1 active site, and the presence of multiple NDM-1 variants are all factors that impede the development of effective NDM-1 inhibitors [4,11,14].

NDM-1 inhibitors are commonly classified as covalent and noncovalent. Noncovalent inhibitors include zinc-binding thiols, bicyclic boronate (taniborbactam) and metal chelating agents, while compounds such as nitroprusside, p-chloromercuribenzoate (p-CMB), cefaclor and ebselen are among the covalent ones [14-24].

From a medicinal chemistry perspective, various scaffolds have been explored for NDM-1 inhibition, including metal chelating agents, cyclic boronate scaffolds and thiol-based scaffolds like captopril and related sulfuric derivatives (carboxymethyl mercaptoacetate thioether, mercaptopropionic acid and ebsulfur). Captopril is a biologically validated scaffold. Although captopril itself is not a clinically suitable NDM-1 inhibitor, crystallographic and medicinal chemistry studies have shown that it provides an effective starting point for optimization [11,25-30,38-43].

In the last decade, several medicinal chemistry studies have investigated captopril-based and captopril-inspired derivatives to enhance potency, selectivity, and binding affinity toward MBLs and NDM-1, specifically. These studies demonstrate the usefulness of the captopril scaffold in the rational design of inhibitors targeting MBLs, NDM-1 and DapE [16,20-22,31-43]. Although an increasing number of studies have been conducted, a systematic synthesis of the existing structure-activity relationship information on captopril-derived NDM-1 inhibitors remains lacking. Thus, the current paper serves as a review and comparative analysis of captopril-based inhibitors, particularly regarding trends in IC50 values and structural characteristics that influence NDM-1 inhibitory activity, and it is anticipated that the findings from this study will facilitate the discovery of NDM-1 inhibitors by providing guidelines for further lead optimization.