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

Objectives: To characterize NAI-107 and related lantibiotics for their in vitro activity against Gram-negative patho- gens, 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.

Methods: We 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 expo- nential and stationary-phase cells. The effects on biofilms (growth inhibition and biofilm eradication) were eval- uated 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.

Results: The results showed that NAI-107 and its brominated variant are highly active against Neisseria gonor- rhoeae and some other fastidious Gram-negative pathogens. Furthermore, all compounds strongly synergized with polymyxin against Acinetobacter baumannii, Escherichia coli, Klebsiella pneumoniae and Pseudomonas aer- uginosa, and showed bactericidal activity. Surprisingly, NAI-107 alone was bactericidal against non-dividingA. 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.