Design, synthesis, and evaluation of novel pleuromutilin aryl acrylate derivatives as promising broad-spectrum antibiotics especially for combatting multi-drug resistant gram-negative bacteria

Abstract

The emergence of drug-resistant strains presents a grave challenge for traditional antibiotics, underscoring the exigency of exploring novel antibacterial drugs. To address this, the present study endeavors to design and synthesize a collection of pleuromutilin aromatic acrylate derivatives, guided by combination principles. The antibacterial activity and structure-activity relationship of these derivatives were evaluated, and most of the derivatives displayed moderate to excellent antibacterial activity against both Gram-positive bacteria and Gram-negative bacteria. Among these derivatives, 5g exhibited the strongest antibacterial activity, with MIC (minimum inhibitory concentration) values ranging from 1-32 μg/mL, and a MIC value against clinically isolated drug-resistant strains of 4-64 μg/mL. Additionally, 5g exhibited negligible cytotoxicity, superior anti-mycoplasma activity, and a greater propensity to perturb bacterial cell membranes. Notably, the administration of 5g resulted in an increased survival rate of MRSA (Methicillin-resistant Staphylococcus aureus)-infected mice, with an ED₅₀ (median effective dose) value of 9.04 mg/kg. These results indicated the potential of 5g to be further developed as an antibacterial drug for the clinical treatment of drug-resistant bacterial infections.

Keywords: Antibiotics; Broad-spectrum; Gram-negative bacteria; Multi-drug resistant bacteria; Pleuromutilin.