S167: Structure and Mechanism of Antibiotic Tailoring Enzymes

The accelerated appearance of pathogenic bacteria, resistant to the existing battery of antibiotics, has focused efforts on the search for novel anti-microbials with broad-spectrum efficacy and low toxicity while providing limited avenues for bacterial drug resistance.  Glycopeptides, such as vancomycin, represent the “antibiotics of last resort” and have been effective in the treatment of drug-resistant bacteria.  However, with the emergence of vancomycin-resistant pathogens, the need for effective therapeutics against these resistant bacteria have escalated.  Lipoglycopeptides, such as teicoplanin, share similar chemical features with glycopeptides but are shown to be bactericidal against some of these resistant strains, and demonstrate improved pharmacokinetic properties relative to their glycopeptide counterparts. 

The modular architecture of the biosynthetic enzymes that catalyze the formation and decoration of lipoglycopeptides can be exploited to yield novel derivative lipoglycopeptide with potential therapeutic application.  Semi-synthetic approaches towards this goal have already yielded two drugs that are in clinical trials. We utilize a combination of chemical, microbiological and structural biological methods to characterize the components of the lipoglycopeptide biosynthetic pathway, with the goal of re-engineering their specificities to generate derivatives that are not accessible through synthetic methods.  These studies should provide proof of principle that novel lipoglycopeptides can be engineered by structure-based principles, and further the application of teicoplanin biosynthetic enzymes in combinatorial biosynthetic chemistry.