ANALYSIS OF SYNTHETIC LANTIBIOTIC ANALOG MUTACIN 1140

University Of Wisconsin-Madison, Madison WI

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Abstract

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The increasing occurrence of multi-drug resistant bacteria has created a dramatic need for the identification and testing of new antibiotics to take the place of those that are failing. Mutacin 1140 is a post-translationally modified peptide antibiotic produced by Streptococcus mutans JH1140 (1). It belongs to a family of antibiotics called lantibiotics because of their unique post-translational modification involving the formation of lanthionine rings. This class of antibiotics has received considerable attention because of the broad spectrum of activity, high potency, low immunogenicity and good structural stability. Importantly, genetically-stable resistant variants of sensitive strains of mutacin 1140 have not yet been found, suggesting that this antibiotic is a good candidate as a therapeutic agent against infection and that the structure and chemistry of mutacin may provide important information for the development of new antibiotics. We have made considerable advances in the understanding of the mechanism of activity of the antibiotic mutacin 1140. Mutacin functions, much like vancomycin, in that it binds to lipid II, which is essential for cell wall formation. Moreover, we have recently reported a novel mechanism of bactericidal activity for mutacin 1140, in which it not only binds to lipid II, but it will trap lipid II into large stable complexes that abduct lipid II from its functional location within the bacteria. It is imperative that we learn more about the structural elements of mutacin 1140 that are important for its bactericidal activity. This information can be used to develop novel antimicrobial compounds.