Semisynthetic polymyxins with potent antibacterial activity and reduced kidney cell toxicity.
Cornelis J Slingerland, Vladyslav Lysenko, Samhita Chaudhuri, Charlotte M J Wesseling, Devon Barnes, Rosalinde Masereeuw, Nathaniel I Martin
Author Information
Cornelis J Slingerland: Biological Chemistry Group, Institute of Biology Leiden, Leiden University Sylviusweg 72 2333 BE Leiden The Netherlands n.i.martin@biology.leidenuniv.nl. ORCID
Vladyslav Lysenko: Biological Chemistry Group, Institute of Biology Leiden, Leiden University Sylviusweg 72 2333 BE Leiden The Netherlands n.i.martin@biology.leidenuniv.nl.
Samhita Chaudhuri: Biological Chemistry Group, Institute of Biology Leiden, Leiden University Sylviusweg 72 2333 BE Leiden The Netherlands n.i.martin@biology.leidenuniv.nl.
Charlotte M J Wesseling: Biological Chemistry Group, Institute of Biology Leiden, Leiden University Sylviusweg 72 2333 BE Leiden The Netherlands n.i.martin@biology.leidenuniv.nl.
Devon Barnes: Division of Pharmacology, Utrecht Institute of Pharmaceutical Sciences, Utrecht University 3584 CG Utrecht The Netherlands.
Rosalinde Masereeuw: Division of Pharmacology, Utrecht Institute of Pharmaceutical Sciences, Utrecht University 3584 CG Utrecht The Netherlands. ORCID
Nathaniel I Martin: Biological Chemistry Group, Institute of Biology Leiden, Leiden University Sylviusweg 72 2333 BE Leiden The Netherlands n.i.martin@biology.leidenuniv.nl. ORCID
The growing incidence of infections caused by multi-drug resistant Gram-negative bacteria has led to an increased use of last-resort antibiotics such as the polymyxins. Polymyxin therapy is limited by toxicity concerns, most notably nephrotoxicity. Recently we reported the development of a novel class of semisynthetic polymyxins with reduced toxicity wherein the N-terminal lipid and diaminobutyric acid residue are replaced by a cysteine-linked lipid featuring a reductively labile disulfide bond. In the present study we further explored the potential of this approach by also varying the amino acid residue directly adjacent to the polymyxin macrocycle. This led to the identification of new semisynthetic polymyxins that maintain the potent antibacterial activity of the clinically used polymyxin B while exhibiting a further reduction in toxicity toward human proximal tubule epithelial cells. Furthermore, these new polymyxins were found to effectively synergize with novobiocin, rifampicin, and erythromycin against -positive, polymyxin resistant .
