Haloduracin

The emergence of drug-resistant pathogens has triggered the search for more efficient antimicrobial agents and formulations for treatment of infections. In recent years, combination therapy has become one of the effective clinical practices in treating infections. The present study deals with the effect of haloduracin, a lantibiotic bateriocin and chloramphenicol against clinically important bacteria. The combined use of haloduracin and chloramphenicol resulted in remarkable synergy against a spectrum of microorganisms including strains of Staphylococcus aureus, Enterococcus faecium, Enterococcus faecalis and different groups of Streptococcus. The synergy allowed using these antimicrobial agents at substantially reduced concentrations without compromising their efficiency. Use of lower doses of chloramphenicol can avoid the severity of its side effects. In addition to minimizing undesirable side effects of some drugs, this approach brings the possibility of using antibiotics that are no longer effective due to drug resistance. Furthermore, the observed synergy between haloduracin and chloramphenicol opens a new window of using bacteriocins and antibiotics in combination therapy of infections.

Bacillus halodurans was cultivated on wheat bran as a solid-state substrate and produced haloduracin, a bacteriocin, at about 245 AU per wheat bran. Supplementation of the bran with Lauria-Bertani broth decreased haloduracin production. However, production was stimulated by addition of Mg(2)SO(4) and K(2)HPO(4). The highest production was achieved at a wheat bran/moisture ratio of 1:1.8 and in the presence of 10% (w/w) Na(2)CO(3). Under optimum conditions, the organism produced about 3,000 AU per gram dry bran.

The two-peptide lantibiotic haloduracin is composed of two post-translationally modified polycyclic peptides that synergistically act on gram-positive bacteria. We show here that Halα inhibits the transglycosylation reaction catalyzed by PBP1b by binding in a 2:1 stoichiometry to its substrate lipid II. Halβ and the mutant Halα-E22Q were not able to inhibit this step in peptidoglycan biosynthesis, but Halα with its leader peptide still attached was a potent inhibitor. Combined with previous findings, the data support a model in which a 1:2:2 lipid II:Halα:Halβ complex inhibits cell wall biosynthesis and mediates pore formation, resulting in loss of membrane potential and potassium efflux.