METAL REPRESSOR TARGETS AND PEPTIDE ACTIVATORS

It is becoming more difficult to treat bacterial infections such as, tuberculosis, staphylococcus, and streptococcus due to the emergence of multiple antibiotic-resistant strains. Rational drug design may prove invaluable for developing new antibiotic agents. Advanced Microbial Solutions Corporation (AMS) developing a new class of anti-microbial agents targeted at metal ion-activated transcriptional repressors. The strategy utilized by AMS uses genetic, biochemical and structural information known about the prototypical repressor of this class, Diphtheria Toxin Repressor, (DtxR) and genetic homologues cloned from a number of different pathogenic bacteria to develop specific anti-microbial drugs. Iron regulation is critical for not only invasion and establishment of the infectious agent but also its survival in the host. The iron-dependent repressor, DtxR, originally cloned from Corynebacterium diphtheriae, binds to specific operator sequences upstream of virulence genes, which control the expression of such products as diphtheria toxin, siderophores and heme-oxygenase. Therefore, controlling the expression of virulence genes through the activation of these metal-dependent regulators can reduce a pathogens ability to survive. The specific aims of this proposal are to begin to define the critical surfaces of the target repressors, which control the iron-dependent phenotype, and to generate second-generation peptide activators.