A Novel Ammonium Carboxylate Salt of Undecylenic Acid for the Topical Treatment of Gram‐Positive and Antibiotic‐Resistant Skin Infections

Uncomplicated topical skin infections like impetigo, caused by gram-positive bacteria such as Staphylococcus aureus and Streptococcus pyogenes, are a common global health issue, particularly affecting children. With increasing antimicrobial resistance, conventional treatments such as mupirocin are becoming ineffective, highlighting the necessity for new antimicrobial development. Fatty acids have long shown potential as novel antimicrobials, but their development has been limited by solubility and efficacy concerns in topical applications. We previously discovered that combining the amino acid L-arginine with an 11-carbon fatty acid, undecylenic acid, produced a water-soluble ammonium carboxylate salt, arginine undecylenate, referred to as GS-1, that elicits potent antimicrobial activity. Under CLSI test conditions, GS-1 showed effective antibacterial activity against clinical isolates of methicillin-sensitive S. aureus (MSSA), methicillin-resistant S. aureus (MRSA), vancomycin-intermediate S. aureus, and S. pyogenes, with MICs of 0.60-1.26 mg/mL and MBCs of 0.63-5.04 mg/mL, respectively. Fluorescence microscopy revealed GS-1 to elicit antibacterial activity by rapidly permeabilising bacterial membranes and inducing reactive oxygen species formation. Serial exposure of 5 MRSA clinical isolates to sub-lethal doses of GS-1 did not appear to induce resistance. In fact, compared to mupirocin, repeated exposures to GS-1 appeared to sensitise bacteria to GS-1. In an animal model of skin infection, topical GS-1 successfully eradicated MRSA from infected, abraded skin after 6 days of treatment with no signs of toxicity. Finally, repeated topical GS-1 exposure in humans caused no irritation or sensitisation. These results support GS-1 as a potential novel topical antibacterial for the treatment of impetigo and other skin infections.