Efficacious Analogs of the Lantibiotic Mutacin 1140 Against a Systemic MRSA Infection [Experimental Therapeutics]

Mutacin 1140, a member of the epidermin family of type AI lantibiotics, has a broad spectrum of activity against Gram-positive bacteria. It blocks cell wall synthesis by binding to lipid II. Although it has rapid bactericidal effects and potent activity against Gram-positive pathogens, its rapid clearance and short half-life in vivo limits its development in clinic. In this study, we evaluated the effect of charged and dehydrated residues on the pharmacokinetics of mutacin 1140. The dehydrated residues were determined to contribute to the stability of mutacin 1140, while alanine substitutions of the lysine or arginine residues improved the pharmacological properties of the antibiotic. Analogs K2A and R13A had a significantly lower clearance, leading to higher plasma concentrations over time. They also had improved bioactivities against several pathogenic bacteria. In a murine systemic MRSA infection model, a 10 mg/kg single intravenous bolus injection of the K2A and R13A analogs (1:1 ratio) protected 100% of infected mice, while a 2.5 mg/kg dose resulted in 50% survival. The 10 mg/kg treatment group had a significant reduction in bacteria load in the liver and kidney, compared to the vehicle control group. The study provides lead compounds for future development of antibiotics used to treat systemic Gram-positive infections.

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