SPR741

1.Novel polymyxin derivatives are less cytotoxic than polymyxin B to renal proximal tubular cells/PMID 22504013; Peptides 2012 Jun; 35(2):248-52/Name matches: nab7061 nab741
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.

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2.Polymyxin Derivatives that Sensitize Gram-Negative Bacteria to Other Antibiotics/PMID 30641878; Molecules (Basel, Switzerland) 2019 Jan; 24(2): (Review Article)/Name matches: nab7061 nab741
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.

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3.The renaissance of polymyxins/PMID 23895690; Current medicinal chemistry 2013; 20(30):3759-73 (Review Article)/Name matches: nab7061 nab741
Abstract:Polymyxins are polypeptide antibiotics, with a primary effect of membrane damaging due to their selective binding to the lipopolysaccharide of Gram-negative bacteria. Their nephro- and neurotoxic side effects limited their use, however, in the last decade the emergence of multidrug-resistant Gram-negative bacteria led to the reintroduction of polymyxins into clinical practice. This review provides an overview about the history and the latest developments of polymyxins. We describe the antimicrobial effects, pharmacodynamics, pharmacokinetics and different routes of administration. We highlight natural classic polymyxins, namely polymyxin B and E, the non-classic agents polymyxin M, S and T. Novel polymyxin chemical structure derivatives will be listed including NAB739, NAB740, NAB741 and NAB7061, that can have important therapeutical role in the future.