Efficacious Analogs of the Lantibiotic Mutacin 1140 against a Systemic Methicillin-Resistant Staphylococcus aureus Infection
| Autor: | Mengxin Geng, Akshaya Ravichandran, Leif Smith, Jerome Escano |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Methicillin-Resistant Staphylococcus aureus medicine.drug_class 030106 microbiology Antibiotics Static Electricity Microbial Sensitivity Tests medicine.disease_cause Arginine Kidney Protein Engineering Microbiology 03 medical and health sciences chemistry.chemical_compound Methicillin Mice Structure-Activity Relationship Bacteriocins In vivo medicine Animals Pharmacology (medical) Experimental Therapeutics Amino Acid Sequence Pharmacology Mice Inbred BALB C Alanine biology Chemistry Protein Stability Lysine Pathogenic bacteria Lantibiotics Staphylococcal Infections biology.organism_classification Methicillin-resistant Staphylococcus aureus Survival Analysis Infectious Diseases Amino Acid Substitution Liver Staphylococcus aureus Drug Design Female Peptides Mutacin 1140 Bacteria |
| Popis: | 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 limit its development in the 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 for the lysine or arginine residues improved the pharmacological properties of the antibiotic. Analogs K2A and R13A had significantly lower clearances, leading to higher plasma concentrations over time. They also had improved bioactivities against several pathogenic bacteria. In a murine systemic methicillin-resistant Staphylococcus aureus (MRSA) infection model, a 10-mg/kg single intravenous bolus injection of the K2A and R13A analogs (1:1 ratio) protected 100% of the 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 livers and kidneys compared to that in the vehicle control group. The study provides lead compounds for the future development of antibiotics used to treat systemic Gram-positive infections. |
| Databáze: | OpenAIRE |
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