Antibacterial and anti-virulence activity of the repurposed agent SX-682 against Staphylococcus aureus

Methicillin-resistant Staphylococcus aureus (MRSA) has become one of the most prevalent drug-resistant pathogens in many countries, posing a serious threat to global healthcare. Consequently, there is an urgent need to develop novel antibacterial agents.

This study aimed to evaluate the antibacterial and antibiofilm activities of SX-682-an orally bioavailable allosteric inhibitor of CXCR1/2-against S. aureus and to elucidate its underlying mechanisms.

Our findings demonstrate that SX-682 exhibits potent antibacterial activity against S. aureus, with minimum inhibitory concentration (MIC) values ranging from 8 to 16 µg/mL. Time-kill curves revealed a concentration-dependent bactericidal effect. Sub-inhibitory concentrations of SX-682 significantly inhibited the formation of S. aureus biofilms and effectively eradicated preformed mature biofilms. SX-682 enhances the membrane permeability of S. aureus and causes depolarization of the membrane potential, thereby damaging the integrity of the bacteria. By suppressing hemolytic activity and staphyloxanthin biosynthesis, SX-682 reduced the virulence of S. aureus. Additionally, proteomic analysis revealed that SX-682 treatment induced dysregulated expression of proteins in S. aureus, including SasG, FnbA, SdrC, SdrD, SaeR, SaeS, and SarX, which are associated with bacterial biofilm formation, bacterial virulence, and amino acid metabolism. Notably, in a murine model of MRSA-infected skin wounds, SX-682 significantly accelerated wound healing.

Collectively, these findings highlight the considerable antibacterial and antibiofilm efficacy of SX-682 against S. aureus, supporting its potential as a promising therapeutic candidate for preventing and treating S. aureus infections.