A biosynthetic engineering approach to elucidating the structure-activity relationship of the enacyloxins

Antibiotics are an essential part of modern medicine, but antimicrobial resistance (AMR) is rapidly neutralising their effectiveness. There is thus an urgent need to develop new antibiotics to overcome the health threat posed by AMR. This is particularly the case for Acinetobacter baumannii, which has recently been identified by the World Health Organisation as one of three "critical priority" pathogens for new antibiotic research and development. Enacyloxin is an antibiotic produced by Burkholderia and Frateuria species with potent activity against Acinetobacter baumanii, including several antibiotic-resistant clinical isolates. To optimise enacyloxin for clinical use, analogues are needed to improve our understanding of its structure-activity relationship. However, the structural complexity of enacyloxin makes such analogues challenging to produce via chemical synthesis. This project aims to exploit recently-developed insights into enacyloxin biosynthesis to produce novel analogues that will illuminate the structure-activity relationship of the antibiotic.