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.
Highlights
Polymyxins (polymyxin B (PMB) and polymyxin E) are cyclic lipodecapeptide antibiotics, highly basic due to five free amino groups, and quite effective against Gram-negative bacteria such as the majority of Enterobacteriaceae as well as Acinetobacter baumannii and Pseudomonas aeruginosa.All members of the polymyxin class contain a cyclic heptapeptide core, linked to a linear tripeptide “panhandle” with an N-terminal fatty acyl moiety (Figure 1)
Their subsequent study revealed that the MIC90 values of clarithromycin in the presence of 8 mg/L of SPR741 were for E. coli (n = 178), K. pneumoniae (n = 115) and E. cloacae (n = 111), 2, 8, and 1 mg/L, respectively [71]
Polymyxins increase the permeability of the outer membrane (OM) to noxious agents but this action is in most instances masked by their direct bactericidal action which takes place at the very same concentrations
Summary
Polymyxins (polymyxin B (PMB) and polymyxin E (colistin)) are cyclic lipodecapeptide antibiotics, highly basic due to five free amino groups, and quite effective against Gram-negative bacteria such as the majority of Enterobacteriaceae as well as Acinetobacter baumannii and Pseudomonas aeruginosa. Certain derivatives of polymyxins have lost their direct bactericidal activity but still damage the OM, restructure it, and weaken its function as a permeability barrier to many butnoxious still damage the OM, restructure it, and weaken its function as a permeability barrier to many agents, including antibiotics [17] They act as “permeabilizers”, “sensitizers”, or noxious agents, including antibiotics [17]. The directly antibacterial polymyxins exhibit potentiating activity at subinhibitory concentrations (see below) but the synergy indices are far lower because of the intrinsic activity of the direct-acting polymyxin derivative itself Quite importantly, it has been shown, in the case of polymyxin B nonapeptide (PMBN, see below), that the stereochemical configuration is a determinant of the OM-damaging effect, since the enantiomer of PMBN lacks this activity [23]. This review sums up the properties of polymyxin derivatives that lack any notably direct antibacterial activity but sensitize the bacteria to other antibiotics
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