Biosynthetic engineering approaches to the creation of novel enacyloxin IIa analogues

"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 which new antibiotics are urgently needed to
overcome resistance to current treatments. Enacyloxin IIa is an antibiotic
produced by Burkholderia species with potent activity against Acinetobacter
baumannii, including antibiotic-resistant clinical isolates, that blocks protein
synthesis by allosterically inhibiting EF-Tu. To optimise enacyloxin for clinical
use, analogues are needed to illuminate its structure-activity relationship and
improve its aqueous solubility and chemical stability. However, the structural
complexity of enacyloxin IIa makes such analogues challenging to produce via
chemical synthesis. This project aims to exploit extensive insights into
enacyloxin IIa biosynthesis generated by the Challis group over more than a
decade to produce novel analogues with improved solubility and stability.
These analogues will enable a more complete assessment of the potential of
enacyloxin IIa to be developed into a into a useful antibiotic for the treatment of
infections caused by A. baumannii."