Tony Velkov
Monash University, Australia
Title: Development of novel antimicrobial lipopeptides against MDR Gram-negative ‘superbugs’
Biography
Biography: Tony Velkov
Abstract
The octapeptins are a family of naturally occurring cyclic lipopeptide antibiotics with a broad antimicrobial spectrum against multidrug-resistant (MDR) Gram-negative and Gram-positive ‘superbugs’. Octapeptins were discovered over 30 years ago, consequently there is limited information on their chemical biology and structure-activity-relationships (SAR). Accordingly, the broad aim of our study is to explore the chemical biology of the octapeptins through a SAR approach. Synthetic chemistry will be employed to generate a large series of novel analogs that will be evaluated against the biological systems the octapeptins are known to modulate. The best approach to achieve this is through the substitution of existing amino acids with novel derivatives rather than chemical modification of the side-chain functionalities. This can only be achieved through a ‘total synthesis’ approach, which is a particularly challenging task considering the complex chemical structure of the octapeptins. To the best of our knowledge, we are the first group to have developed an efficient routine ‘total synthesis’ of octapeptins on a scale that would allow for mechanistic investigations of antibacterial activity and resistance. For the first time our novel approach will interface the chemistry and biology of these important antibiotic compounds to investigate the underlying SAR with the purpose of creating new functions. More specifically the ultimate aim is to med-chem out liabilities such as nephrotoxicity whilst concomitantly improving the antimicrobial activity and spectrum, thereby creating the foundations for a new generation of safer and more efficacious antibiotics.