Membrane-targeted antibiotic for complicated skin and skin structure (cSSSI) infections caused by MRSA, VISA and VRE (methicillin and Vancomycin-resistant S. aureus and enterococci).

The aim of this research programme is to develop a best in class antibiotic, which in this application we term Vancapticin, for intravenously administered treatment of community acquired and nosocomial Grampositive complicated skin and skin structure infections (cSSSI) and pneumonia (CAP/NP). The drug candidate will have superior efficacy, broader spectrum of action (especially against resistant bacteria) and a more favourable therapeutic index than its direct competitors: Vancomycin, Teicoplanin, Telavancin, Daptomycin, Linezolid and Tigecycline. In 2008, these marketed drugs had combined sales of US$2.4 billion, with Vancomycin responsible for US$0.7 billion of these sales. This will be achieved by chemical modification of the out-of-patent antibiotic Vancomycin with membraneselective elements that target the drug to membranes of Gram-positive bacteria, in preference to those of human cells. Preliminary work (~100 compounds synthesised to date) indicates that this strategy is highly effective in selecting for potent anti-infective agents suitable for intravenous administration. These proof-ofconcept compounds possess vastly improved activity profiles against a variety of susceptible and resistant bacteria. Our pilot compounds are 10- to 100-fold more active than other glycopeptides, are bactericidal and act by additional modes of action: enhanced inhibition of bacterial transglycosylases and disruption of bacterial membrane integrity.