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Molecules 2019, 24(2), 249; https://doi.org/10.3390/molecules24020249

Polymyxin Derivatives that Sensitize Gram-Negative Bacteria to Other Antibiotics

Northern Antibiotics, Espoo, Finland and Department of Bacteriology and Immunology, Helsinki University Medical School, Helsinki, Finland
Tekniikantie 14 (Technopolis, Innopoli 2), Suite A111, FIN-00150 Espoo, Finland.
Received: 9 December 2018 / Revised: 27 December 2018 / Accepted: 7 January 2019 / Published: 11 January 2019
(This article belongs to the Special Issue Polymyxins)
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Abstract

Polymyxins (polymyxin B (PMB) and polymyxin E (colistin)) are cyclic lipodecapeptide antibiotics, highly basic due to five free amino groups, and rapidly bactericidal against Gram-negative bacteria, such as the majority of Enterobacteriaceae as well as Acinetobacter baumannii and Pseudomonas aeruginosa. Their clinical use was abandoned in the 1960s because of nephrotoxicity and because better-tolerated drugs belonging to other antibiotic classes were introduced. Now, due to the global dissemination of extremely-drug resistant Gram-negative bacterial strains, polymyxins have resurged as the last-line drugs against those strains. Novel derivatives that are less toxic and/or more effective at tolerable doses are currently under preclinical development and their properties have recently been described in several extensive reviews. Other derivatives lack any direct bactericidal activity but damage the outermost permeability barrier, the outer membrane, of the target bacteria and make it more permeable to many other antibiotics. This review describes the properties of three thus far best-characterized “permeabilizer” derivatives, i.e., the classic permeabilizer polymyxin B nonapeptide (PMBN), NAB7061, and SPR741/NAB741, a compound that recently successfully passed the clinical phase 1. Also, a few other permeabilizer compounds are brought up. View Full-Text
Keywords: polymyxin B nonapeptide (PMBN); NAB7061; SPR741/NAB741; Enterobacteriaceae; Acinetobacter baumannii; Pseudomonas aeruginosa; synergism; permeabilizers; clinical phase 1 study polymyxin B nonapeptide (PMBN); NAB7061; SPR741/NAB741; Enterobacteriaceae; Acinetobacter baumannii; Pseudomonas aeruginosa; synergism; permeabilizers; clinical phase 1 study
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Vaara, M. Polymyxin Derivatives that Sensitize Gram-Negative Bacteria to Other Antibiotics. Molecules 2019, 24, 249.

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