title: Novel polymyxin derivatives are less cytotoxic than polymyxin B to renal proximal tubular cells.
abstract: The emergence of very multiresistant Gram-negative bacterial strains has reinstated polymyxins (polymyxin B, colistin), pentacationic lipopeptides, in the therapy, in spite of their nephrotoxicity. Extensive tubular reabsorption concentrates polymyxin in proximal tubular cells. The novel polymyxin derivatives NAB739, NAB7061 and NAB741 have their cyclic part identical to that of polymyxin B, but their side chain consists of uncharged octanoyl-threonyl-d-serinyl, octanoyl-threonyl-aminobutyryl, and acetyl-threonyl-D-serinyl respectively. In this study, we compared the toxicities of NAB739, NAB7061 and NAB741 with that of polymyxin B by using the porcine renal proximal tubular cell line LLC-PK1 electroporated or incubated with the selected compound. Both the ability to cause cell necrosis (quantified as the leakage of lactate dehydrogenase) and the ability to cause apoptosis (as quantified by counting apoptotic nuclei) were assessed. In electroporated cells, polymyxin B induced total (>85%) necrosis of the cells at 0.016 mM, whereas an approx. 8-fold concentration of NAB739 and NAB7961 and an approx. 32-fold concentration of NAB741 was required for the same effect. In cells treated without electroporation (incubated), polymyxin B elicited a marked degree (approx. 50%) of necrosis at 0.5mM, whereas the NAB compounds were inert even at 1mM. Neither polymyxin B nor the NAB compounds induced apoptosis.
authors.affiliation: Louvain Drug Research Institute, Pharmacologie Cellulaire et Moléculaire, Université Catholique de Louvain, Brussels, Belgium.
authors.forename: Marie-Paule
authors.initials: MP
authors.lastname: Mingeot-Leclercq
authors.forename: Paul M
authors.initials: PM
authors.lastname: Tulkens
authors.forename: Sophie
authors.initials: S
authors.lastname: Denamur
authors.forename: Timo
authors.initials: T
authors.lastname: Vaara
authors.forename: Martti
authors.initials: M
authors.lastname: Vaara
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D018274:Electroporation; D006090:Gram-Negative Bacteria / Q000187:drug effects; D007668:Kidney / Q000187:drug effects* / Q000473:pathology; D007687:Kidney Tubules, Proximal / Q000187:drug effects*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D009336:Necrosis; D011112:Polymyxin B / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity*; D011113:Polymyxins / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity*; D013552:Swine
chemical_list: D000900:Anti-Bacterial Agents; C546018:NAB 7061 peptide; C546019:NAB 739 peptide; C553640:NAB741; D011113:Polymyxins; D007770:L-Lactate Dehydrogenase; D011112:Polymyxin B