1. Peptides. 2012 Jun;35(2):248-52. Epub 2012 Apr 6.

Novel polymyxin derivatives are less cytotoxic than polymyxin B to renal proximal
tubular cells.

Mingeot-Leclercq MP, Tulkens PM, Denamur S, Vaara T, Vaara M.

Louvain Drug Research Institute, Pharmacologie Cellulaire et Moléculaire,
Université Catholique de Louvain, Brussels, Belgium.

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.

Copyright © 2012 Elsevier Inc. All rights reserved.

PMID: 22504013  [PubMed - in process]