Nathaniel Holman

Protein 0-glycosylation enzymes as targets for novel antimicrobials against mycobacteria

Biography: I graduated from the University of York in 2015 with a first class BSc degree in Biochemistry (with a year in industry). During my degree, I spent 12 months at AstraZeneca’s Alderley Park site where I worked on in vitro toxicological screening of newly synthesised compounds. I am currently in the first year of my PhD which aims to address the growing problem of antimicrobial resistance under the supervision of Professors Maggie Smith and Tony Wilkinson.

Project introduction: Tuberculosis is caused by Mycobacterium tuberculosis and was responsible for roughly 1.5 million deaths in 2014. M. tuberculosis is a member of the Actinobacteria family that includes Corynebacterium spp. and the Streptomyces spp. These bacteria all have a protein glycosylation pathway involving a polyprenol phosphate mannose synthase (Ppm1) and a protein mannosyl transferase (Pmt). Importantly, mutants of M. tuberculosis that lack this pathway are either sick or dead and in Streptomyces (and Corynebacteria) mutations in the glycosylation enzymes lead to antibiotic hypersensitive phenotypes. Taken together, these observations indicate that the enzymes in the protein glycosylation pathway are excellent targets for novel antimicrobials.

Project objectives: Our goal is to understand the structure and mechanism of the protein glycosylation enzymes with a view to identifying novel inhibitors. Preliminary data indicate that the Streptomyces Ppm1 is most likely to yield a 3-dimensional structural model of this enzyme. The structure will then be used to guide a screen for inhibitors using a fragment based approach. In parallel we will also investigate the biophysical properties of Ppm1 and its structure-function relationships by mutation and in vivo phenotypic analysis.