Excretion of the Polymyxin Derivative NAB739 in Murine Urine.

Extremely multiresistant strains of Enterobacteriaceae are emerging and spreading at a worrisome pace. Polymyxins are used as the last-resort therapy against such strains, in spite of their nephrotoxicity. We have previously shown that novel polymyxin derivatives NAB739 and NAB815 are less nephrotoxic in cynomolgus monkeys than polymyxin B and are therapeutic in murine pyelonephritis at doses only one-tenth of that needed for polymyxin B.

Corrigendum: Polymyxins and Their Potential Next Generation as Therapeutic Antibiotics.

[This corrects the article DOI: 10.3389/fmicb.2019.

Polymyxins and Their Potential Next Generation as Therapeutic Antibiotics.

The discovery of polymyxins, highly basic lipodecapeptides, was published independently by three laboratories in 1947. Their clinical use, however, was abandoned in the sixties because of nephrotoxicity and because better-tolerated drugs belonging to other antibiotic classes were discovered. Now polymyxins have resurged as the last-resort drugs against extremely multi-resistant strains, even though their nephrotoxicity forces clinicians to administer them at doses that are lower than those required for optimal efficacy.

The polymyxin derivative NAB739 is synergistic with several antibiotics against polymyxin-resistant strains of Escherichia coli, Klebsiella pneumoniae and Acinetobacter baumannii.

The antibiotic crisis has reinstated polymyxins, once abandoned because of their toxicity. Now, preclinical studies have revealed better tolerated and more effective derivatives of polymyxins such as NAB739. Simultaneously, polymyxin-resistant (PMR) strains such as the mcr-1 strains have received lots of justified publicity, even though they are still very rare.

Human kidney on a chip assessment of polymyxin antibiotic nephrotoxicity.

Drug-induced kidney injury, largely caused by proximal tubular intoxicants, limits development and clinical use of new and approved drugs. Assessing preclinical nephrotoxicity relies on animal models that are frequently insensitive; thus, potentially novel techniques - including human microphysiological systems, or "organs on chips" - are proposed to accelerate drug development and predict safety. Polymyxins are potent antibiotics against multidrug-resistant microorganisms; however, clinical use remains restricted because of high risk of nephrotoxicity and limited understanding of toxicological mechanisms.

New polymyxin derivatives that display improved efficacy in animal infection models as compared to polymyxin B and colistin.

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.

Polymyxin derivatives NAB739 and NAB815 are more effective than polymyxin B in murine Escherichia coli pyelonephritis.

Objectives: Extremely multiresistant strains of Enterobacteriaceae, such as those of Escherichia coli and Klebsiella pneumoniae, are emerging and spreading at a worrisome speed. Polymyxins (polymyxin B, colistin) are used as last-line therapy against such strains, in spite of their notable nephrotoxicity that may even require discontinuation of the therapy. We have previously developed polymyxin derivatives NAB739 and NAB815 that are better tolerated in cynomolgus monkeys than polymyxin B and are, in contrast to polymyxin B, excreted in the cynomolgus urine to a very significant degree.

Structure-activity studies on polymyxin derivatives carrying three positive charges only reveal a new class of compounds with strong antibacterial activity.

Recent years have brought in an increased interest to develop improved polymyxins. The currently used polymyxins, i.e.