Inhibition of β-lactamase by Novel Benzothiazole-Coupled Azetidinone Derivatives: A Comprehensive Study Using an In silico and In vitro Approaches Against Multi Drug Resistant Bacteria

Abstract

Anti-microbial resistance has emerged as the leading cause of death worldwide with the rise of multidrug-resistant (MDR) bacteria, the need for novel anti-microbials to treat serious illnesses has become a great necessity. Hence, in this study, we aimed to design and synthesize benzothiazole-coupled azetidinone derivatives (GD1–GD12) as novel antibacterial agents. The synthesized compounds were elucidated by nuclear magnetic resonance, infrared and mass spectroscopy. The antibacterial activities of these compounds were tested against antibiotic-susceptible and MDR strains of bacteria. In addition, we performed ADME profiling, molecular docking and molecular dynamic simulations, principle component analysis, dynamic cross-correlation map and free-energy landscape to assess the binding of synthesized compounds with the [Formula: see text]-lactamase. Among the synthesized compounds GD6 and GD5 displayed minimum inhibitory concentrations of 12.5 [Formula: see text]g/mL and 50 [Formula: see text]g/mL against MDR strains of E. coli; more effective than standard. The molecular docking of designed molecules was performed against [Formula: see text]-lactamase enzyme and the stability of the complex was validated. The pharmacokinetic profile displayed the compounds to possess druggable properties within the suitable ranges. The in silico approach displayed compound GD6 to be stable with [Formula: see text]-lactamase enzyme; indicating the mechanism for these compounds to be via inhibition of [Formula: see text]-lactamase. The novel anti-microbial compounds assessed against susceptible and MDR strains of bacteria possess antibacterial potential via the inhibition of [Formula: see text]-lactamase. The aforementioned data will be crucial to the development of novel broad-spectrum antibacterial compounds.