The novel pyridine-fused quinolinone PQ-L5 exhibits antibacterial effects and enhances β-lactam activity by targeting PBP2a in methicillin-resistant Staphylococcus aureus.

Abstract

Background: Infections caused by methicillin-resistant Staphylococcus aureus (MRSA) are becoming increasingly difficult to treat because of the resistance of this pathogen to multiple drugs and its ability to form biofilms. Therefore, the development of new antimicrobial agents to combat MRSA infections is urgently needed.

Methods: We designed and synthesized a series of structurally novel pyridine-fused quinolinones via a one-pot method, and compound PQ-L5 which exhibited excellent antibacterial activity against gram-positive bacteria, especially MRSA strains was selected for further study. The bactericidal activity, synergistic antibacterial effect and antibiofilm activity of PQ-L5 were investigated, and then its in vitro cytotoxicity and in vivo anti-MRSA efficacy were evaluated.

Results: PQ-L5 displayed rapid bactericidal activity without inducing resistance even after continuous passage. The mechanistic study revealed that PQ-L5 inhibited peptidoglycan biosynthesis by binding to PBP2a, disrupting the bacterial cell wall and ultimately resulting in bacterial death. Furthermore, PQ-L5 restored the susceptibility of MRSA to β-lactam antibiotics and could inhibit the biofilm formation of different MRSA strains at sub-MIC concentrations both alone and in combination with oxacillin. In addition, PQ-L5 had low hemolytic activity and cytotoxicity in vitro, and in a mouse skin tissue infection model, PQ-L5 alone or in combination with oxacillin at a low dose reduced the MRSA load in wounds and enhanced the process of wound healing.

Conclusions: PQ-L5 might be a promising antimicrobial agent against MRSA infections and that the synergistic effect of PQ-L5 combined with β-lactams reduces the required dosages of these drugs and thus minimizes potential toxic side effects.