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Animal Model of Implant-Associated Infections in Mice
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New polymyxin derivatives that display improved efficacy in animal infection models as compared to polymyxin B and
Martti Vaara1,2
1Northern Antibiotics Ltd., Espoo, Finland.
Abstract:
Polymyxin B and colistin (polymyxin E) are bactericidal pentacationic lipopeptides that act specifically on Gram-negative bacteria, first by disrupting their outermost permeability barrier, the outer membrane (OM), and then damaging the cytoplasmic membrane. The discovery of both polymyxin B and colistin was published independently by three laboratories as early as in 1947. They were subsequently used in intravenous therapy. Unfortunately, they also exhibit significant and dose-limiting nephrotoxicity. Therefore, polymyxins were reserved as agents of last-line defense. The emergence of extremely multiresistant strains has now forced clinicians to reinstate polymyxins in the therapy of severe infections. However, the current dosage regimens lead to insufficient drug concentrations in serum and clinicians have been advised to use larger doses, which further increases the risk of nephrotoxicity. Very recently, the interest in developing better tolerated and more effective polymyxins has grown. This review focuses on describing four development programs that have yielded novel derivatives that are more effective than the old polymyxins in animal infection models. Compounds from three programs are superior to the old polymyxins in the rodent lung infection model with Acinetobacter baumannii and/or Pseudomonas aeruginosa. One of them is also more effective than polymyxin B in A. baumannii mouse thigh infection. The fourth program includes compounds that are approximately tenfold more effective in Escherichia coli murine pyelonephritis than polymyxin B.
Insights
Novel polymyxin derivatives show enhanced efficacy against Gram-negative bacterial infections in animal models, offering a promising alternative to older drugs with reduced toxicity. These advancements address the urgent need for effective treatments against multidrug-resistant bacteria.
Area of Science:
- Microbiology
- Pharmacology
- Infectious Diseases
Background:
- Polymyxins (Polymyxin B and colistin) are critical antibiotics for treating Gram-negative bacterial infections.
- Their use is limited by dose-dependent nephrotoxicity and emerging bacterial resistance.
- Increasing multidrug resistance necessitates the development of improved polymyxin formulations.
Purpose of the Study:
- To review recent development programs focused on novel polymyxin derivatives.
- To evaluate the efficacy of these new compounds in preclinical infection models.
- To identify polymyxin derivatives with improved therapeutic profiles.
Main Methods:
- Review of four distinct polymyxin derivative development programs.
- Assessment of compound efficacy in various animal infection models, including Acinetobacter baumannii and Pseudomonas aeruginosa.
- Comparative analysis of novel derivatives against established polymyxins (Polymyxin B).
Main Results:
- Three development programs yielded derivatives more effective than older polymyxins in rodent models of Acinetobacter baumannii and/or Pseudomonas aeruginosa lung infections.
- One derivative demonstrated superior efficacy to Polymyxin B in a mouse model of Acinetobacter baumannii thigh infection.
- A fourth program produced compounds with significantly enhanced efficacy in a murine pyelonephritis model against Escherichia coli.
Conclusions:
- Novel polymyxin derivatives exhibit superior efficacy in preclinical models compared to existing polymyxins.
- These advancements hold potential for improved treatment of severe Gram-negative bacterial infections.
- Further development is warranted to address toxicity and resistance challenges.
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