Discovery of Unique Bis-Substituted Aromatic Amide Derivatives as Novel Highly Potent Antibiotics for Combating Methicillin-Resistant Staphylococcus aureus (MRSA)

Due to the increasing antibiotic resistance, developing novel antimicrobials to fight infections caused by resistant bacteria is imperative. Herein, a series of novel bis-substituted aromatic amides were designed and synthesized through modifying the hit compound 1, and their antimicrobial activities were evaluated. Among them, compound 4t, as the most potent lead, exhibited excellent antimicrobial activities against Gram-positive bacteria, including clinical methicillin-resistant Staphylococcus aureus (MRSA) isolates, while keeping weak hemolytic and mammalian cytotoxic activities. Furthermore, compound 4t displayed rapid bactericidal capabilities, low tendency to produce resistance, and favorable capacities to destroy bacterial biofilms. Further explorations indicated that compound 4t induces bacterial death by binding to cardiolipin (CL) on the bacterial membrane, disrupting the cell membrane, and facilitating the accumulation of reactive oxygen species (ROS). Additionally, compound 4t showed remarkable anti-MRSA activity in vivo, demonstrating compound 4t could be developed as a potential candidate to combat MRSA infections.