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Membrane-disorganizing property of polymyxin B nonapeptide
Abstract:
The possibility of improving the antibacterial activities of drugs normally excluded by Gram-negative bacteria with polymyxin B nonapeptide (PMBN) has been explored. In vitro, PMBN rendered clindamycin, erythromycin, novobiocin, rifampicin and vancomycin very active against a number of Gram-negative enteric bacteria. The drug also sensitized the previously resistant bacterial strains to human, mouse or guinea pig serum. However, parenterally administered PMBN failed to influence bacterial growth in chambers implanted into mice and guinea pigs. It was also ineffective in experimental septicaemia at a dose of up to 200 mg/kg or when combined with antibiotics with which it interacted synergistically in vitro.
Insights
Polymyxin B nonapeptide (PMBN) enhanced antibiotic activity against Gram-negative bacteria in vitro. However, PMBN showed limited efficacy in vivo for treating bacterial infections in animal models.
Area of Science:
- Microbiology
- Pharmacology
- Infectious Diseases
Background:
- Gram-negative bacteria possess outer membranes that restrict the entry of many antibiotics.
- Polymyxin B nonapeptide (PMBN) is a derivative of polymyxin B known to interact with bacterial membranes.
Purpose of the Study:
- To investigate the potential of PMBN to enhance the antibacterial activity of various drugs against Gram-negative bacteria.
- To evaluate the in vivo efficacy of PMBN in combination with antibiotics in animal models of infection.
Main Methods:
- In vitro susceptibility testing of Gram-negative enteric bacteria exposed to antibiotics with and without PMBN.
- Serum sensitization assays using human, mouse, and guinea pig serum.
- In vivo studies using implanted chambers in mice and guinea pigs to assess bacterial growth.
- Experimental septicaemia models in animals to evaluate therapeutic efficacy.
Main Results:
- PMBN significantly enhanced the in vitro activity of clindamycin, erythromycin, novobiocin, rifampicin, and vancomycin against Gram-negative bacteria.
- PMBN sensitized resistant bacterial strains to complement-mediated lysis by serum from multiple species.
- Parenteral administration of PMBN did not inhibit bacterial growth in vivo.
- PMBN was ineffective in treating experimental septicaemia, even at high doses or in combination with synergistic antibiotics.
Conclusions:
- PMBN demonstrates potent in vitro synergistic activity with various antibiotics against Gram-negative bacteria.
- Despite promising in vitro results, PMBN exhibits limited therapeutic value in vivo for Gram-negative infections.
- Further research is needed to overcome the in vivo limitations of PMBN for potential clinical applications.