Sulfamethoxazole-phytochemical hybrid: A novel approach in current antibacterial drug development

Abstract

Background: The Gram-positive (GP) bacterium, methicillin-resistant Staphylococcus aureus (MRSA) causes common infection, bacteremia at hospitals, and community sectors, with the simultaneous aggrandizement of resistance to several currently used antibacterials, resulting in additional morbidity and unexpected mortality. Since the last several decades, thousands of phytochemicals with antimicrobial potency have been recorded as alternate antibacterial agents; but, none of those have gone up to the pure-drug stage due to the lack of the desired drug-likeness values and the required pharmacokinetic properties. However, chemical modification of parent drug remains as the versatile approach in antibacterial drug development. Methods and materials: Based on the structural suitability of sulfamethoxazole (SMZ) and as a solution towards control of MRSA, proposed six new ‘SMZ-phytochemical’ hybrid entities followed by protocol of azo-coupling synthesis. PASS prediction, Lipinski rules of five, lethal-dose value, toxicity class, and molecular docking-simulation were employed before chemical synthesis. Due to the unavailability of the three-dimensional (3D) structure of the suitable target enzyme, MRSA-dihydropteroate synthases (DHPS), the 3D model of MRSA-DHPS was generated and validated by the Ramachandran plot for molecular docking-simulations study with designed hybrids. Based on the above computational analyses, the most effective hybrid, ‘SMZ-thymol,’ was synthesized and characterized by advanced spectral techniques such as UV, FTIR, LCMS, HPLC, NMR, and SEM. The zone of inhibition, MIC, and MBC values of the hybrid had determined against isolated MRSA strain from clinical samples, in vitro. Results: The synthesized ‘SMZ-thymol’ hybrid had the highest zone size inhibition on agar plates with 20 and 40 μg/mL as the lowest MIC and MBC values against MRSA, respectively, while the reference antibiotic ampicillin had the lower MIC and MBC values at 80 to 180 μg/mL. Additionally, from in vitro host-toxicity testing with cultured human lymphocytes from umbilical cord blood confirmed that the synthesized hybrid had broadly, non-toxic to human cells. Conclusion: Thus, newly synthesized ‘SMZ-thymol’ could be promoted as a newer antibacterial agent against gruesome MRSA and other MDR pathogenic bacteria. Indeed, the utilization of inactive antibacterials through suitable phytochemicals in the current antibacterial drug development module could be a prudent time-killing drug development approach using tools of medicinal chemistry and bioinformatics.