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Causes of polymyxin treatment failure and new derivatives to fill the gap
Selena Chiu1, Anna M Hancock1, Bob W Schofner2
1Department of Chemical and Biological Engineering, Princeton University, Princeton, NJ, USA.
Abstract:
Polymyxins are a class of antibiotics that were discovered in 1947 from programs searching for compounds effective in the treatment of Gram-negative infections. Produced by the Gram-positive bacterium Paenibacillus polymyxa and composed of a cyclic peptide chain with a peptide-fatty acyl tail, polymyxins exert bactericidal effects through membrane disruption. Currently, polymyxin B and colistin (polymyxin E) have been developed for clinical use, where they are reserved as "last-line" therapies for multidrug-resistant (MDR) infections. Unfortunately, the incidences of strains resistant to polymyxins have been increasing globally, and polymyxin heteroresistance has been gaining appreciation as an important clinical challenge. These phenomena, along with bacterial tolerance to this antibiotic class, constitute important contributors to polymyxin treatment failure. Here, we review polymyxins and their mechanism of action, summarize the current understanding of how polymyxin treatment fails, and discuss how the next generation of polymyxins holds promise to invigorate this antibiotic class.
Insights
Polymyxins are crucial antibiotics for treating Gram-negative infections but face rising resistance. Understanding polymyxin resistance and tolerance is key to overcoming treatment failures and developing new therapies.
Area of Science:
- Microbiology
- Pharmacology
- Infectious Diseases
Background:
- Polymyxins, discovered in 1947, are peptide antibiotics effective against Gram-negative bacteria.
- Polymyxins B and E (colistin) are last-line treatments for multidrug-resistant infections.
- Increasing global resistance and heteroresistance to polymyxins pose significant clinical challenges.
Purpose of the Study:
- To review polymyxins, their mechanism of action, and reasons for treatment failure.
- To discuss the growing issue of polymyxin resistance and bacterial tolerance.
- To explore the potential of next-generation polymyxins in combating resistant infections.
Main Methods:
- Literature review of polymyxin antibiotics.
- Analysis of mechanisms of action and resistance.
- Discussion of clinical challenges and future therapeutic strategies.
Main Results:
- Polymyxins kill bacteria by disrupting cell membranes.
- Treatment failures are linked to increasing resistance, heteroresistance, and bacterial tolerance.
- Next-generation polymyxins offer potential solutions to overcome current limitations.
Conclusions:
- Polymyxin resistance is a critical threat to treating Gram-negative infections.
- Further research into resistance mechanisms and novel polymyxin development is essential.
- Next-generation polymyxins show promise for revitalizing this important class of antibiotics.
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