Expanding the potential of NAI-107 for treating serious ESKAPE pathogens: synergistic combinations against Gram-negatives and bactericidal activity against non-dividing cells

Abstract

ObjectivesTo characterize NAI-107 and related lantibiotics for their in vitro activity against Gram-negative pathogens, alone or in combination with polymyxin, and against non-dividing cells or biofilms of Staphylococcus aureus. NAI-107 was also evaluated for its propensity to select or induce self-resistance in Gram-positive bacteria.MethodsWe used MIC determinations and chequerboard experiments to establish the antibacterial activity of the examined compounds against target microorganisms. Time–kill assays were used to evaluate killing of exponential and stationary-phase cells. The effects on biofilms (growth inhibition and biofilm eradication) were evaluated using biofilm-coated pegs. The frequency of spontaneous resistant mutants was evaluated by either direct plating or by continuous sub-culturing at 0.5 × MIC levels, followed by population analysis profiles.ResultsThe results showed that NAI-107 and its brominated variant are highly active against Neisseria gonorrhoeae and some other fastidious Gram-negative pathogens. Furthermore, all compounds strongly synergized with polymyxin against Acinetobacter baumannii, Escherichia coli, Klebsiella pneumoniae and Pseudomonas aeruginosa, and showed bactericidal activity. Surprisingly, NAI-107 alone was bactericidal against non-dividing A. baumannii cells. Against S. aureus, NAI-107 and related lantibiotics showed strong bactericidal activity against dividing and non-dividing cells. Activity was also observed against S. aureus biofilms. As expected for a lipid II binder, no significant resistance to NAI-107 was observed by direct plating or serial passages.ConclusionsOverall, the results of the current work, along with previously published results on the efficacy of NAI-107 in experimental models of infection, indicate that this lantibiotic represents a promising option in addressing the serious threat of antibiotic resistance.

Interbacterial mechanisms of colonization resistance and the strategies pathogens use to overcome them

“…However, recent work examining the bacteriocin NAI-107 found that this lantibiotic has activity against a small number of fastidious Gram-negative pathogens, and synergizes with polymyxin to inhibit a broader range of Gram-negative pathogens including Klebsiella pneuomoniae , and E. coli . 69 Several groups have also attempted to artificially broaden the range of targets of bacteriocins. 70,71 For example, Nisin that had been complexed to carbon and gold nanoparticles with a net positive charge had increased access to the periplasm of Gram-negative bacteria and antibacterial activity against E. coli and Pseudomonas aeruginosa.…”

Polymyxin Derivatives that Sensitize Gram-Negative Bacteria to Other Antibiotics

“…Other interesting compounds include the lantibiotic NAI-107, consisting of 23 amino acyl residues. It has been shown to be very synergistic with polymyxin B against Enterobacteriaceae and A. baumannii [84].…”

Systematic characterization of position one variants within the lantibiotic nisin

“…Upon leader peptide cleavage, the lantibiotic becomes activated and exhibits antimicrobial activity with efficiencies in the low nanomolar to millimolar range. Lantibiotics like NAI-107 or NVB302 are already subjected to pre-clinical trails and might be good candidates in the treatment of multidrug-resistant strains like MRSA or similar Gram-positive strains 5–7 .…”