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Engineering lipoglycopeptide biosynthesis to produce new antibiotics

Project Description

There is an urgent need for new antibiotics to combat antimicrobial resistance. Most antibiotics originate from Streptomyces bacteria, however the low hanging fruit from this resource has been picked. Genome sequencing projects have revealed that an average actinomycete harbours ~30-50 biosynthetic pathways, but unfortunately the majority of these are not expressed in the laboratory. The promise that these silent or cryptic metabolites hold has ushered in a genomics-driven renaissance in natural product antibiotic discovery.

In this project, you will characterise key steps in the biosynthesis of one such cryptic antibiotic, a novel lipoglycopeptide which we have discovered after activation of one of these biosynthetic pathways. You will use structural approaches to characterise the key glycosyl-lipid transferase that installs an essential lipidated sugar and use this to guide rational engineering of the enzyme to change the sugar and lipid components of the metabolite. Using this structure-activity relationship you will identify the antibiotic with the highest activity against clinical isolates of multidrug-resistant Staphylococcus aureus.

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Funding Notes

White Rose BBSRC Doctoral Training Partnership in Mechanistic Biology
4 year fully-funded programme of integrated research and skills training, starting Oct 2019:
• Research Council Stipend
• UK/EU Tuition Fees
• Conference allowance
• Research Costs

At least a 2:1 honours degree or equivalent. We welcome students with backgrounds in biological, chemical or physical sciences, or mathematical backgrounds with an interest in biological questions.
EU candidates require 3 years of UK residency in order to receive full studentship

Not all projects advertised will be funded; the DTP will appoint a limited number of candidates via a competitive process.

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Zhiwei Q, Munnoch JT, Devine R, Holmes NA, Seipke RF, Wilkinson KA, Wilkinson B, Hutchings MI. 2017. Formicamycins, antibacterial polyketides produced by Streptomyces formicae isolated from African Tetraponera plant-ants. Chemical Science 8:3218-3227
McLean TC, Hoskisson PA, Seipke RF. 2016. Coordinate regulation of antimycin and candicidin. mSphere 1:e00305-16
Liu J, Zhu X, Seipke RF, Zhang W. 2015. Biosynthesis of antimycins with a reconstituted 3-formamidosalicylate pharmacophore in Escherichia coli. ACS Synth Biol 54:559-565
Seipke RF, Patrick E, Hutchings MI. 2014. Regulation of antimycin biosynthesis by the orphan ECF RNA Polymerase sigma factor σAntA. PeerJ 2:e253

Frandsen KEH, Simmons TJ, Dupree P, Poulsen JCN, Hemsworth GR, Ciano L, Johnston EM, Tovborg M, Johansen KS, Freiesleben von P, Marmuse L, Fort S, Cottaz S, Driguez H, Henrissat B, Lenfant N, Tuna F, Baldansuren A, Davies, GJ., Lo Leggio L, Walton PH. 2016 The molecular basis of polysaccharide cleavage by lytic polysaccharide monooxygenases. Nat Chem Biol. 12:298–303
Hemsworth GR, Johnston EM, Davies GJ, Walton PH. 2015. Lytic Polysaccharide Monooxygenases in Biomass Conversion. Trends Biotechnol 33:747–761
Hemsworth GR, Henrissat B, Davies GJ, Walton PH. 2014. Discovery and characterization of a new family of lytic polysaccharide monooxygenases. Nat Chem Biol 10:122–126
Hemsworth GR, Taylor EJ, Kim RQ, Gregory RC, Lewis SJ, Turkenburg JP, Parkin A, Davies GJ, Walton PH. 2013. The copper active site of CBM33 polysaccharide oxygenases. J Am Chem Soc. 135:6069–6077

Arnott ZLP, Nozaki S, Monteiro DCF, Morgan HE, Pearson AR, Niki H, Webb ME. 2017. Mechanism of regulation of pantothenate biosynthesis by the PanD-PanZ.AcCoA complex reveals an additional mode of action for the antimetabolite N-pentyl pantothenamide (N5-Pan). Biochemistry doi: 10.1021/acs.biochem.7b00509
Morrison PM, Balmforth MR, Ness SW, Williamson DJ, Rugen MD, Turnbull WB, Webb ME. 2016. Confirmation of a protein-protein interaction in the pantothenate biosynthetic pathway using sortase-mediated labelling. Chembiochem 17:753-758
Monteiro DC, Patel V, Bartlett CP, Nozaki S, Grant TD, Gowdy JA, Thompson GS, Kalverda AP, Snell EH, Niki H, Pearson AR, Webb ME. 2015. The Structure of the PanD/PanZ Protein Complex Reveals Negative Feedback Regulation of Pantothenate Biosynthesis by Coenzyme A. Chem. Biol 22:492-503
Morrison PM, Foley PJ, Warriner SL, Webb ME. 2015. Chemical generation and modification of peptides containing multiple dehydroalanines. Chem Commun 51:13470-13473

How good is research at University of Leeds in Biological Sciences?

FTE Category A staff submitted: 60.90

Research output data provided by the Research Excellence Framework (REF)

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