Objective Enacyloxin IIa is a polyketide antibiotic with activity against Gram-positive and Gram-negative bacteria that targets ribosomal elongation factor Tu. It has recently been identified as metabolite of Burkholderia ambifaria AMMD and shown to have clinically-relevant activity against Acinetobacter baumannii, a problematic pan-resistant Gram-negative pathogen. Despite its promising biological activity, enacyloxin IIa has not been used in the clinic, presumably due to stability issues. Preliminary experiments have provided evidence for an unusual mechanism of modular polyketide synthase chain release in enacyloxin biosynthesis, involving intermolecular condensation of an acyl carrier protein (ACP)-bound thioester with the C-3 hydroxyl group of (1R, 3R, 4S)-3,4-dihydroxycyclohexane carboxylic acid (DHCCA). The resulting intermediate undergoes epimerisation at C-1 of the DHCCA moiety. This project aims to explore the ability of the chain release enzyme to catalyse the acetylation of a variety of DHCCA analogues with an acetyl-ACP analogue of the polyketide thioester intermediate. It also aims to identify the enzyme responsible for epimerising C-1 of the DHCCA moiety. DHCCA biosynthetic genes will be deleted in B. ambifaria and enacyloxin analogues, with a stable amide group in place of the labile ester group and other modifications to the DHCCA-derived moiety, will be produced via a mutasynthesis strategy. Fields of science natural scienceschemical sciencesorganic chemistryorganic acidsmedical and health sciencesclinical medicinecritical care medicinemedical and health sciencesbasic medicinepharmacology and pharmacypharmaceutical drugsantibioticsmedical and health sciencesbasic medicinepharmacology and pharmacydrug resistancemultidrug resistancenatural sciencesbiological sciencesbiochemistrybiomoleculesproteinsenzymes Programme(s) H2020-EU.1.3. - EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions Main Programme H2020-EU.1.3.2. - Nurturing excellence by means of cross-border and cross-sector mobility Topic(s) MSCA-IF-2014-EF - Marie Skłodowska-Curie Individual Fellowships (IF-EF) Call for proposal H2020-MSCA-IF-2014 See other projects for this call Funding Scheme MSCA-IF-EF-ST - Standard EF Coordinator THE UNIVERSITY OF WARWICK Net EU contribution € 195 454,80 Address Kirby Corner Road - University House CV4 8UW Coventry United Kingdom See on map Region West Midlands (England) West Midlands Coventry Activity type Higher or Secondary Education Establishments Links Contact the organisation Opens in new window Website Opens in new window Participation in EU R&I programmes Opens in new window HORIZON collaboration network Opens in new window Total cost € 195 454,80
