Recent Chemical Candidates for Tackling Antibiotics- Resistance Crisis Caused by Metallo-β-Lactamases

Antibiotic resistance had been one of the major risks of the healthcare system since early 2000 [1]. After the early 1980s, the number of new antibiotics developed and approved is kept on decreasing while the number of antibiotic resistant strains are on increase due to overuse of antibiotics and international human and animal mobility [2]. When the number of clinically available antibiotics is limited by antibiotic resistance, co-administrating conventional antibiotics with compounds that reverse resistance is an effective approach [3]. In this regard, many β-lactamase inhibitors (BLIs), which reverse resistance against one of the most widely used β-lactam antibiotics [4], are developed. However, until now there is no effective inhibitor for metallo-β-lactamases (MBLs), which have a distinct mechanism and structure from serine-β-lactamases (SBLs). This is a problem when there is a global prevalence of MBL producing Enterobacteriaceae and P. aeruginosa strains [5]. In this mini-review article, we will look into some of the most recent (2019-2021) researches regarding MBL inhibitor development to facilitate researches and help find new research objectives. Compounds were sorted into categories according to the criteria of main mechanism of action. Compound’s characteristics were summarized with emphasis on the mechanism of action, β-lactam (carbapenem) potentiating activity, and measured/expected cytotoxicity.

Keywords:Metallo-β-lactamase, MBL, β-lactamase, β-lactamase Inhibitor, BLI, Antibiotics

Abbreviations: Metallo-β-Lactamase, BLI – Β-Lactamase Inhibitor, NDM – New delhi MBL, VIM - Verona integron MBL, IMP – Imipenemase, SBL – Serine-β-Lactamase, PBP – Penicillin Binding Protein, OM – Outer membrane, CRE - Carbapenem-Resistant Enterobacteriaceae, SPM - São Paulo MBL, GIM – German Imipenemase, CphA – Carbapenem hydrolyzing and first (A) from Aeromonas hydrophila, L1 – Labile enzyme, OXA - Active on oxacillin, B1, B2, B3 – β-lactamase of Ambler Class B subclass 1, 2, 3, MPC – Minimum Potentiating Concentration, MIC – Minimum Inhibitory Concentration, MBC – Minimum Bactericidal Concentration, PK, PD – Pharmaco-Kinetics/Dynamics, AMA - Aspergillomarasmine A, PMPCs – 6-Phosphonomethylpyridine-2-carboxylates, DM- N-[2-(dansylamino)ethyl] maleimide, CAMP – Cyclic Antimicrobial Peptide, SLAY - Surface Localization Antimicrobial display, MTT assay – Tetrazolium dye assay. Used to measure cytotoxicity in hRBC in mentioned article, BC – Red blood cell, MMP - matrix metalloproteinases, SICLOPPS - split intein mediated circular ligation of peptides and proteins, PEP4 - Peptidomimetic 4, MCR - mobilized colistin resistance, (Meropenem susceptibility) Breakpoint – By CLSI definition, MIC bigger than 4 mg/L for Enterobacteriaceae, and 8 mg/L for P. aeruginosa strains. By EUCAST definition, MIC bigger than 8 mg/L for both strains