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A Facile and Efficient Approach for the Production of Reversible Disulfide Cross-linked Micelles
Published on: December 23, 2016
Synthesis and Evaluation of Polymyxins Bearing Reductively Labile Disulfide-Linked Lipids
Cornelis J Slingerland1, Charlotte M J Wesseling1, Paolo Innocenti1
1Biological Chemistry Group, Institute of Biology Leiden, Leiden University, Sylviusweg 72, 2333 BE Leiden, The Netherlands.
Abstract:
Polymyxins are a class of lipopeptide anti-infective agents with potent and specific activity against Gram-negative bacteria. While toxicity concerns associated with polymyxin B and E (colistin) have historically limited their clinical application, today they are increasingly used as last-resort antibiotics given the rise of multidrug-resistant Gram-negative pathogens. The adverse side effects of polymyxins are well known, particularly as related to their nephrotoxicity. Here, we describe the synthesis and evaluation of a novel series of polymyxin analogues, aimed at reducing their nephrotoxic effects. Using a semisynthetic approach, we explored modifications of the exocyclic part of the polymyxin scaffold, namely, the terminal amino acid and lipophilic tail. By incorporating a reductively labile disulfide linkage in the lipid tail, we obtained novel polymyxins that exhibit potent antibacterial activity on par with polymyxin B but with reduced toxicity toward human renal proximal tubular epithelial cells.
Insights
Researchers developed new polymyxin antibiotics to combat drug-resistant Gram-negative bacteria. These novel polymyxin analogues show potent antibacterial activity with significantly reduced kidney toxicity.
Area of Science:
- Microbiology
- Medicinal Chemistry
- Pharmacology
Background:
- Polymyxins are crucial last-resort antibiotics against multidrug-resistant Gram-negative bacteria.
- Nephrotoxicity is a major dose-limiting adverse effect of polymyxins, restricting their clinical use.
- The rise of antimicrobial resistance necessitates the development of safer and effective polymyxin derivatives.
Purpose of the Study:
- To synthesize and evaluate novel polymyxin analogues with reduced nephrotoxicity.
- To explore modifications in the exocyclic region of the polymyxin scaffold.
- To maintain potent antibacterial activity while mitigating kidney damage.
Main Methods:
- Semisynthetic approach to modify polymyxin structure.
- Incorporation of a reductively labile disulfide linkage in the lipid tail.
- Evaluation of antibacterial activity and cytotoxicity against human renal cells.
Main Results:
- Novel polymyxin analogues synthesized and characterized.
- The modified polymyxins retained potent antibacterial activity comparable to polymyxin B.
- Reduced toxicity was observed in human renal proximal tubular epithelial cells.
Conclusions:
- The novel polymyxin analogues represent a promising advancement in antibiotic development.
- Disulfide linkage modification offers a strategy to reduce polymyxin-induced nephrotoxicity.
- These findings could lead to safer therapeutic options for multidrug-resistant infections.
