New polymyxin derivatives that display improved efficacy in animal infection models as compared to polymyxin B and colistin

Abstract

Polymyxin B and colistin (polymyxin E) are bactericidal pentacationic lipopeptides that act specifically on Gram-negative bacteria, first by disrupting their outermost permeability barrier, the outer membrane (OM), and then damaging the cytoplasmic membrane. The discovery of both polymyxin B and colistin was published independently by three laboratories as early as in 1947. They were subsequently used in intravenous therapy. Unfortunately, they also exhibit significant and dose-limiting nephrotoxicity. Therefore, polymyxins were reserved as agents of last-line defense. The emergence of extremely multiresistant strains has now forced clinicians to reinstate polymyxins in the therapy of severe infections. However, the current dosage regimens lead to insufficient drug concentrations in serum and clinicians have been advised to use larger doses, which further increases the risk of nephrotoxicity. Very recently, the interest in developing better tolerated and more effective polymyxins has grown. This review focuses on describing four development programs that have yielded novel derivatives that are more effective than the old polymyxins in animal infection models. Compounds from three programs are superior to the old polymyxins in the rodent lung infection model with Acinetobacter baumannii and/or Pseudomonas aeruginosa. One of them is also more effective than polymyxin B in A. baumannii mouse thigh infection. The fourth program includes compounds that are approximately tenfold more effective in Escherichia coli murine pyelonephritis than polymyxin B.

The polymyxin derivative NAB739 is synergistic with several antibiotics against polymyxin-resistant strains of Escherichia coli, Klebsiella pneumoniae and Acinetobacter baumannii

“…It has long been known that polymyxins increase the permeability of the OM and permeabilize it to other drugs. This property is most easily recognizable with derivatives such as polymyxin B nonapeptide (PMBN), NAB7061 and NAB741 that lack any direct antibacterial activity [15,16,[18][19][20]32,35], Several other polycationic peptides, such as linear lipopeptide paenipeptins and unacylated tridecaptin share this property of polymyxins and drastically sensitize the target bacteria to rifampin [36,37], clarithromycin [36], and many other antibiotics [37]. Besides the traditional antibiotics, certain novel antibiotics under development, such as the lantibiotic NAI-107, are synergistic with polymyxins [38].…”

“…In a murine E.coli pyelonephritis model, NAB739 was effective at a dose one tenth of that of PMB, even though the MIC of NAB739 against the challenge strain was higher than that of PMB (2 mg/L vs. 0.5 mg/L) [17]. Furthermore, NAB739 is less nephrotoxic to cynomolgus monkeys than PMB [16].…”

“…Since complicated urinary tract infections (cUTI) caused by XDR strains and proceeding to septic shock are a major concern, compounds like NAB739 may be clinically useful. In a 7-day cynomolgus monkey study, NAB739 yielded at equal doses urinary concentrations ten-fold compared to those of PMB [16]. In a murine E.coli pyelonephritis model, NAB739 was effective at a dose one tenth of that of PMB, even though the MIC of NAB739 against the challenge strain was higher than that of PMB (2 mg/L vs. 0.5 mg/L) [17].…”

“…A plausible explanation for the synergism is that even though the PMR strains can grow at higher concentrations of polymyxins than the polymyxin-susceptible wild-type strains, subinhibitory concentrations of polymyxins are still able to damage the outermost permeability barrier, the outer membrane (OM) of the PMR bacteria. Consequently, the damaged OM allows the entry of drugs normally excluded or partially excluded by the intact enterobacterial OM [13,14] NAB739 is a novel polymyxin derivative [15,16]. It carries only three positive groups, all in strategic positions, instead of five in PMB and colistin (Table 1).…”

“…Herein we show that NAB739 acts against PMR strains synergistically with rifampin, the classic compound used in polymyxin synergism studies [15,16,[18][19][20]. Additionally, we report synergism with retapamulin, a pleuromutilin antibiotic and surrogate of lefamulin [21], an antibiotic effective against Gram-positive bacteria only and currently in late clinical development by Nabriva Therapeutics for both oral and intravenous administration [22].…”