Characterization of the Lantibiotic Salivaricin A2 and Design of an Effective Lantibiotic Mutacin 1140 Analog with In Vivo Efficacy
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Date
2019-02-11
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Abstract
Lantibiotics are a class of lanthionine-containing, ribosomally synthesized and post-translationally modified peptides (RiPPs) with antimicrobial activities, and are among the most promising candidates of alternative antibiotics for combatting the emergence of multi-drug resistant bacteria. Two lantibiotics, salivaricin A2 and mutacin 1140, will be presented in this study.
Salivaricin A2, a type AII lantibiotic, is considered to kill Gram-positive bacteria by binding to the cell wall precursor lipid II via a conserved ring A structure. In this study, we characterized the covalent structure of salivaricin A2, supporting the predicted lanthionine and methyllanthionine ring formations present in this structural class of lantibiotics. Removal of the N-terminal Lys1 and Arg2 residues from the peptide causes a dramatic shift in the chemical shift values of amino acid residues seven through nine, suggesting that the N-terminal amino acids contribute to a distinct structural conformer for the linear peptide region. The creation of N-terminal analogs of salivaricin A2 revealed that the antibacterial activity of salivaricin A2 is not only due to the presence of the positively charged N-terminal amino acid residues, but the length of the N-terminal linear peptide is also important for its activity.
Mutacin 1140 belongs to the epidermin family of type AI lantibiotics and it has rapid bactericidal effects and potent activity against Gram-positive pathogens. However, 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 bioactivity, PTM modification, and pharmacokinetics of mutacin 1140. Analogs with improved bioactivity against pathogenic bacteria, increased protease stability, and higher product yields were identified. Through intravenous injection in a mouse model, analogs K2A and R13A demonstrated significantly improved pharmacokinetic properties. In a murine systemic lethal 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 study provides lead compounds for future development of antibiotics used to treat systemic Gram-positive infections.
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Lantibiotics, Salivaricin A2, Mutacin 1140