Design and synthesis of dehydrocurvularin analogues as antibacterial and anti-biofilm agents

Developing highly effective antibacterial agents for treating methicillin-resistant Staphylococcus aureus (MRSA) infections, especially those linked to biofilms, remains a tough problem. Here, we rationally designed and synthesized 30 novel derivatives derived from 10, 11-dehydrocurvularin through biomimetic structural modulation. Compound A25 was chosen as a candidate based on structure-activity relationship analyses against S. aureus and four clinical MRSA isolates (MIC = 2-4 μg/mL), exhibiting minimal resistance development, quickly killed bacteria, and low hemolytic activity (HC₅₀ > 200 μg/mL). Mechanistic investigations demonstrated that A25 selectively targets bacterial membranes by binding phosphatidylethanolamine (PE), thereby disrupting membrane polarization, elevating intracellular ROS levels, and ultimately killing bacteria. Furthermore, compound A25 showed significant anti-biofilm activity against S. aureus, highlighting its potential as a highly promising novel therapeutic candidate for combating MRSA infections.