New drugs, old scaffold: new antimicrobials against bacterial folate biosynthesis Lynden Rooms University of Bristol, UK Folate is a key one-carbon transfer cofactor essential for organisms across biology. As humans, we intake folate via our diets, but in the case of bacteria, fungi, and lower eukaryotes, folate is biosynthesised in numerous enzymatic cascades. As such, targeting the folate production pathway has proven a fruitful route to the development of novel antimicrobials for nearly a century. Abyssomicin C is a type 1 spirotetronate polyketide antibiotic first isolated in 2004 from Micromonspora maris , a marine actinomycete. It is proposed to bind irreversibly to aminodeoxychorismate synthase component 1 (PabB) and is a potent antimicrobial agent against Gram positive bacteria and mycobacteria. There have been several cytotoxicity issues reported, however, and several derivatives with favourable characteristics have been produced via fully synthetic routes to overcome this. Over this 12-month fellowship, I aim to produce a modified version of the natural producer via Crispr based gene silencing and use this modified strain to produce a suite of abyssomicin C derivatives via a new semi synthetic route. It is hoped that, by building on structural data collected over the course of my Ph. D., a rational drug design approach can improve the activity of this promising natural scaffold. References 1. J. Riedlinger et al.Abyssomicins, inhibitors of the para-aminobenzoic acid pathway produced by the marine Verrucosispora strain AB-18-032. J. Antibiot. 57 , 271-279 (2004) 2. E. Gottardi et al. Abyssomicin biosynthesis: formation of an unusual polyketide, antibiotic feeding studies and genetic analysis. ChemBioChem 12 , 1401-1410 (2011) 3. S. Keller et al. Action of atrop-abyssomicin C as an inhibitor of 4-amino-4-deoxychorismate synthase PabB. Ange. Chem. Int. Ed. 46 , 8284-8266 (2007) 4. C. Sadaka et al.Review on abyssomicins: Inhibitors of the chorismate pathway and folate biosynthesis. Molecules 23 , 1371 (2018)
P65
© The Author(s), 2022
Made with FlippingBook Learn more on our blog