Antibiotic resistance is the growing concern and major threat to human health. β-lactamases are important class of enzymes present in bacteria that can efficiently hydrolyse the β-lactam ring thereby rendering the antibiotics ineffective. β-lactamases are classified into four major classes. Classes A, C, and D encompasses serine residue in its active site and promotes catalysis (Bush and Jacoby 2010; Öztürk et al. 2015); whereas, class B possess two zinc metal ions for hydrolysis of antibiotics which therefore referred to as metallo-β-lactamases (MBLs) (Palzkill 2013). His120, His122 and His189 are Zn1 co-ordinating residues, whereas Asp124, Cys208 and His250 are Zn2 co-ordinating amino acid residues (Gandra et al. 2016). The MBL encoding genes can spread between bacteria through horizontal transfer mechanism, thereby converting non-resistant bacteria to resistant bacteria. These enzymes can even potentially degrade carbapenems, which is considered as last line of defence for the treatment against pathogenic bacteria (Feng et al. 2017).
Carbapenem resistance (CR) in Gram-negative organisms is increasing over the years across the globe, reported with high morbidity and mortality rates (Snyder et al. 2019). Molecular mechanisms of CR are due to production of acquired carbapenemases that degrades carbapenem and/or chromosomal mediated loss of porins as well as over-expression of efflux pumps. Carbapenemase mediated resistance is a major concern, as they rapidly disseminate through mobile genetic elements. Very few agents like Colistin, Tigecycline and Fosfomycin are being used for CR infections. Due to the limited therapeutic options, inhibitor molecules are discovered to be partnered with a suitable beta lactam agent, in turn to act against several classes of beta lactamases including carbapenemases.
Newer Beta Lactam/Beta Lactamase Inhibitors (BL/BLIs) agents includes: Ceftazidime/Avibactam, Ceftolozane/Tazobactam, Aztreonam/Avibactam, Imipenem/Relebactam, Meropenem/Vaborbactam, Cefepime/Zidebactam and Meropenem/Nacubactam (Veeraraghavan et al. 2018). These agents work against specific type of carbapenemases with majority being active against Class-A carbapenemases (KPC). However, NDM and Class-D oxacillinases (Oxa-48 like) are endemic in Indian settings (Veeraraghavan et al. 2017) with limited utility of these newer agents. The blaNDM−1 gene and its variants is located on plasmids harbouring multiple resistant determinants, thereby conferring extensive drug resistance, leaving only a few or no therapeutic options that require rapid development of inhibitors (Mathur et al. 2017, 2018; Shankar et al. 2019). As NDM is highly endemic across Indian subcontinent (Lee et al. 2016), it is the need of the hour to have active MBL inhibitors for the management of pathogen infestations. Our research group has extensively worked in the field in-silico prediction of antimicrobial therapeutics and structural biology to understand the protein-ligand interaction against pathogenic microbes (Basu et al. 2020, 2021; Thillainayagam et al. 2020).
D-Captopril is a carboxylic acid based compound that found to be having antagonistic effect on the activity of NDM-1 (Wang et al. 2018). Thus, the screening of D-Captopril analogues using virtual tools and trusted databases (Kim et al. 2016) could shed light on the inhibitor design and effective treatment of pathogenic bacteria carrying NDM-1 and its variants.