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

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 textg/mL and 50 Formula: see textg/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 vali-dated. 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.