NHMRC Research Fellowship (PRF): New antibiotics and treatment methods against drug-resistant bacteria (2014–2018)
Abstract:
We have produced a pipeline of new antibiotics, assays and reagents in the fight against lifethreatening `superbugs'. We will extend this basic science into development and clinical translation, to the benefit of patients who desperately
need better diagnosis and treatment of bacterial infections.
We have developed core competency in the chemical synthesis and characterisation of glycopeptide & lipopeptide antibiotics; drugs that target
membrane-associated components in bacteria. The lab has unique capability to carry out i) high-throughput chemistry to rapidly produce hundreds of variant antibiotics, ii) screens against key human pathogens in high throughput format (384-well MIC & MBC assays), iii) methods to profile interactions with known cognate bacterial targets, and iv) sequence resistant isolates to identify novel secondary targets using whole
genome sequencing. We will focus on three key scaffolds: a) vancomycin, which binds to lipid II, b) friulimicin, which binds to undecaprenol phosphate (C55-P) and c) the lipopeptides polymyxin and octapeptin, which bind to Lipid A. The research will deliver: 1. An IND-enabling data package for Phase I clinical trials of a new antibiotic indicated as a daily dosed monotherapy for patients with G+ve complicated skin and skin structure infections (cSSSI), community acquired and nosocomial pneumonia (CAP/NP). 2. A detailed scientific understanding of the origins and mechanisms of antibiotic-induced nephrotoxicity, and a model for the mode of action lipopeptide derivatives with NDM-1 polymyxin-susceptible and -resistant strains. 3. Candidate lipopeptide antibiotics against resistant G-ve `super-bugs¿ with better safety profiles than current `last-resort' antibiotics such as colistin. 4. A breakthrough method to rapidly and sensitively detect bacterial
contamination. 5. A method for treating bacteremia and septic shock by extracorporeal hemoperfusion. 6. A new chemoinformatic model for the discovery of new antibiotics.
