This displacement permeabilises the Gram negative outer membrane to allow the polymyxins, or other cationic peptides, to form pores [18]. It should be noted, however, that the use of polymyxins in clinical settings has been restricted to use only where drug resistant pathogens have been encountered. This is due to the toxicity, primarily nephro- and neuro-toxicity,

associated with its use [19], although this toxicity has been suggested to be dose dependent [20]. Nonetheless, the polymyxins are, in many cases, the only antibiotics capable of overcoming specific drug resistant pathogens such as Pseudomonas aeruginosa and Acinetobacter baumannii in cystic fibrosis patients (for reviews VRT752271 clinical trial see [21–23]). For this reason the polymyxins cannot be ignored, but strategies that could reduce the dose needed for these antibiotics to be effective are highly desirable. A number of studies have investigated the consequences of combining various antibiotics with polymyxins. Antimicrobial agents such as miconazole [24], rifampicin [25, 26] meropenem, ampicillin-sulbactam, ciprofloxacin, piperacillin-clavulanic acid, imipenem, amikacin, and gentamicin [27] ciprofloxacin [28] trimethoprim, trimethoprim-sulfamethoxazole, and vancomycin [29], to name but a few, have been click here the focus of studies to assess if they can work synergistically with polymyxins (also see Yahav et. al., for a review of compounds

synergistic with polymyxin E [30]). To date the only lantibiotic to have been investigated in this way is nisin, which displays synergy Ribonucleotide reductase with polymyxin B and polymyxin E against Listeria and E. coli[31, 32]. Nisin has also been shown to function synergistically when combined with polymyxin E (and clarithromycin) against Pseudomonas aeruginosa[33]. Combination studies have also recently revealed that lacticin 3147 and the lactoperoxidase system (LPOS) successfully inhibited growth of Cronobacter spp. in rehydrated infant Poziotinib in vitro formula [34]. Lacticin 3147, like nisin, is a food grade bactericidal agent obtained from the GRAS

organism Lactococcus lactis. Notably, however, it differs from nisin with respect to its target specificity and its greater potency against a number of species [10]. Also the mechanism of action contrasts from the single nisin peptide, in that it requires the interaction of two peptides, Ltnα and Ltnβ, for optimal bactericidal activity. Here, we report the first study to investigate whether synergy can occur between polymyxin(s) and a two-component lantibiotic. Not only do we reveal that synergy is apparent against a range of strains tested, we also investigated the individual contributions of Ltnα and Ltnβ. We established that, when combined with polymyxin B/E, the levels of lacticin 3147 required to inhibit Gram negative species are equivalent or lower than the levels of lacticin 3147 alone against many Gram positive targets. Thus, in the presence of 0.