Dr Luke Alderwick PhD

Dr Luke Alderwick

School of Biosciences
Honorary Lecturer in Molecular Microbiology

Contact details

Telephone
+44 (0)121 41 45472
Fax
+44 (0)121 41 45925
Email
l.alderwick@bham.ac.uk
View my research portal
Address
School of Biosciences
University of Birmingham
Edgbaston
Birmingham
B15 2TT
UK

Dr Alderwick is an Honorary Lecturer in Molecular Microbiology in the School of Biosciences. His research group are interested in the biochemistry and molecular genetics that govern cell envelope assembly in Mycobacterium tuberculosis, the causative agent of human TB infection. Dr Alderwick is also the Director of the Birmingham Drug Discovery Facility, a state-of-the-art High Throughput Screening (HTS) laboratory for early stage drug discovery. 

Qualifications

BSc (University of Birmingham)

PhD (University of Birmingham)

Biography

After graduating from the University of Birmingham in 2003 with first class honours degree in BSc Biochemistry, Dr Alderwick continued his academic training in situ, progressing from PhD graduate to Lecturer in Molecular Microbiology. His PhD studies carried out under the supervision of Prof Gurdyal Besra and centred on uncovering the molecular genetics and biochemistry of cell wall assembly in Mycobacterium tuberculosis.

The research carried out during his PhD training culminated in 5 scientific publications and he was subsequently awarded the Dr S. W, Challinor Prize for the best PhD thesis of the 2007. Many of his results generated during his PhD formed the basis of a Wellcome Trust program grant, which was successfully awarded and enabled Dr Alderwick to remain in the lab and continue his post-doctoral research investigating the molecular processes behind complex cell wall polysaccharide biosynthesis in mycobacteria. In 2010, Dr Alderwick was appointed to the position of Lecturer in Molecular Microbiology in the School of Bioscience. In 2012, Dr Alderwick was made Director of the Birmingham Drug Discovery facility.

Research

Research Theme

Molecular Microbiology

Cell wall biosynthesis and assembly in Mycobacterium tuberculosis

Tuberculosis (TB) affects a third of the worlds population and causes 1.7 million deaths annually. Mycobacterium tuberculosis, the causative agent of TB, has a unique cell envelope which differs substantially from the cell wall of both Gram-negative and Gram-positive bacteria. This accounts for its unusual low permeability and hence, contributes to resistance against common antibiotics. The main structural element consists of a cross-linked network of peptidoglycan (PG) in which some of the muramic acid residues are substituted with a complex polysaccharide, arabinogalactan (AG), attached to which are long chain mycolic acids (Figure 1 below).

Aspects of mycobacterial cell wall biosynthesis remain fragmented, particularly those associated with mechanisms of PG biosynthesis and how the cell wall is 'stitched' together. A broad aim of my research involves understanding the mechanisms of mycobacterial PG biosynthesis and how this crucial cell wall structure is recycled during dormancy. Furthermore, I am also interested in how large polysaccharide structures are translocated and covalently attached to the mycobacterial cell wall. Biochemical and structural analysis of these crucial enzymes will shed new light on how mycobacteria assembles its murein sacculus. It will also provide invaluable information regarding subtle alterations that are present in mycobacterial PG, which could reveal potential mechanisms for inhibition and the eventual pursuit of new therapies targeted towards dormant TB infection.

The advent of multi-dug and extensively-drug resistant TB means there has never been a greater need to identify new novel drug targets.


Figure 1

The M. tuberculosis cell wall is composed of peptidoglycan (PG), arabinogalactan (AG), mycolic acids and lipoglycans such as phosphoinositolmannosides (PIM), lipomannan (LM)  and lipoarabinomannan (LAM). Other cell wall associated lipids include trehalose dimycolate (TDM), trehalose monomycolate (TMM), sulpholipids (SL), phthiocerol dimycocerosate (PDIM) and di-acyl trehalose (DAT).

Funding

Research in my laboratory is funded by project grants from the Biotechnology and Biological Sciences Research Council (BBSRC) and Medical Research Council (MRC) Confidence in Concept fund.

The University of Birmingham Drug Discovery and Screening Facility

Dr Alderwick is the Director of the University of Birmingham Drug Discovery and Facility. This £700k investment provides a cutting-edge research facility which is located in the School of Biosciences at the Institute of Microbiology and Infection (IMI). The state-of-the-art lab enables our world-leading research groups to undertake cutting-edge drug discovery research in areas such as infectious diseases and cancer. Academia has contributed immensely in advancing the frontiers of science related to fundamental medical research. However, it has generally been ”Big Pharma” that has translated this research into the discovery and development of new drugs. The primary reason for this disparity has been the cost of the various facets of modern drug discovery, particularly the necessary equipment to quickly and efficiently carry out screening experiments in a high throughput capacity.

Other activities

Dr Alderwick is a keen cyclist and has various other sporting interests, which include football, rugby and golf. When he’s not busy working he enjoys listening to contemporary music, but spends most of his free time at home with friends and family.

Publications

O'Donoghue EJ, Sirisaengtaksin N, Browning DF, Bielska E, Hadis M, Fernandez-Trillo F, Alderwick L, Jabbari S, Krachler AM. Lipopolysaccharide structure impacts the entry kinetics of bacterial outer membrane vesicles into host cells. PLoS Pathog. 2017 Nov 29;13(11):e1006760. doi: 10.1371/journal.ppat.1006760. eCollection 2017 Nov. PubMed PMID: 29186191; PubMed Central PMCID: PMC5724897.

AlAmri MA, Kadri H, Alderwick LJ, Simpkins NS, Mehellou Y. Rafoxanide and Closantel Inhibit SPAK and OSR1 Kinases by Binding to a Highly Conserved Allosteric Site on Their C-terminal Domains. ChemMedChem. 2017 May 9;12(9):639-645. doi: 10.1002/cmdc.201700077. Epub 2017 Apr 12. PubMed PMID: 28371477.

Jankute M, Alderwick LJ, Noack S, Veerapen N, Nigou J, Besra GS. Disruption of Mycobacterial AftB Results in Complete Loss of Terminal β(1 → 2) Arabinofuranose  Residues of Lipoarabinomannan. ACS Chem Biol. 2017 Jan 20;12(1):183-190. doi: 10.1021/acschembio.6b00898. Epub 2016 Dec 5. PubMed PMID: 28033704; PubMed Central PMCID: PMC5259755.

Kadri H, Alamri MA, Navratilova IH, Alderwick LJ, Simpkins NS, Mehellou Y. Towards the Development of Small-Molecule MO25 Binders as Potential Indirect SPAK/OSR1 Kinase Inhibitors. Chembiochem. 2017 Mar 2;18(5):460-465. doi: 10.1002/cbic.201600620. Epub 2017 Jan 30. PubMed PMID: 28004876.

Harrison J, Lloyd G, Joe M, Lowary TL, Reynolds E, Walters-Morgan H, Bhatt A,  Lovering A, Besra GS, Alderwick LJ. Lcp1 Is a Phosphotransferase Responsible for  Ligating Arabinogalactan to Peptidoglycan in Mycobacterium tuberculosis. MBio. 2016 Aug 2;7(4). pii: e00972-16. doi: 10.1128/mBio.00972-16. PubMed PMID: 27486192; PubMed Central PMCID: PMC4981717.

Lambert C, Cadby IT, Till R, Bui NK, Lerner TR, Hughes WS, Lee DJ, Alderwick LJ, Vollmer W, Sockett RE, Lovering AL. Ankyrin-mediated self-protection during cell invasion by the bacterial predator Bdellovibrio bacteriovorus. Nat Commun. 2015 Dec 2;6:8884. doi: 10.1038/ncomms9884. Erratum in: Nat Commun. 2016;7:10483. Sockett, Elizabeth R [Corrected to Sockett, R Elizabeth]. PubMed PMID: 26626559;  PubMed Central PMCID: PMC4686830.

Alderwick LJ, Harrison J, Lloyd GS, Birch HL. The Mycobacterial Cell Wall--Peptidoglycan and Arabinogalactan. Cold Spring Harb Perspect Med. 2015 Mar  27;5(8):a021113. doi: 10.1101/cshperspect.a021113. Review. PubMed PMID: 25818664; PubMed Central PMCID: PMC4526729.

Gurcha SS, Usha V, Cox JA, Fütterer K, Abrahams KA, Bhatt A, Alderwick LJ, Reynolds RC, Loman NJ, Nataraj V, Alemparte C, Barros D, Lloyd AJ, Ballell L, Hobrath JV, Besra GS. Biochemical and structural characterization of mycobacterial aspartyl-tRNA synthetase AspS, a promising TB drug target. PLoS One. 2014 Nov 19;9(11):e113568. doi: 10.1371/journal.pone.0113568. eCollection 2014. PubMed PMID: 25409504; PubMed Central PMCID: PMC4237437.

Jankute M, Byng CV, Alderwick LJ, Besra GS. Elucidation of a protein-protein interaction network involved in Corynebacterium glutamicum cell wall biosynthesis as determined by bacterial two-hybrid analysis. Glycoconj J. 2014 Oct;31(6-7):475-83. doi: 10.1007/s10719-014-9549-3. PubMed PMID: 25117516; PubMed Central PMCID: PMC4213368.

Bacon J, Alderwick LJ, Allnutt JA, Gabasova E, Watson R, Hatch KA, Clark SO,  Jeeves RE, Marriott A, Rayner E, Tolley H, Pearson G, Hall G, Besra GS, Wernisch  L, Williams A, Marsh PD. Non-replicating Mycobacterium tuberculosis elicits a reduced infectivity profile with corresponding modifications to the cell wall and extracellular matrix. PLoS One. 2014 Feb 6;9(2):e87329. doi: 10.1371/journal.pone.0087329. eCollection 2014. PubMed PMID: 24516549; PubMed Central PMCID: PMC3916317.

Grover S, Alderwick LJ, Mishra AK, Krumbach K, Marienhagen J, Eggeling L, Bhatt A, Besra GS. Benzothiazinones mediate killing of Corynebacterineae by blocking decaprenyl phosphate recycling involved in cell wall biosynthesis. J Biol Chem. 2014 Feb 28;289(9):6177-87. doi: 10.1074/jbc.M113.522623. Epub 2014 Jan 20. PubMed PMID: 24446451; PubMed Central PMCID: PMC3937683.

Capeness MJ, Lambert C, Lovering AL, Till R, Uchida K, Chaudhuri R, Alderwick LJ, Lee DJ, Swarbreck D, Liddell S, Aizawa S, Sockett RE. Activity of Bdellovibrio hit locus proteins, Bd0108 and Bd0109, links Type IVa pilus extrusion/retraction status to prey-independent growth signalling. PLoS One. 2013 Nov 5;8(11):e79759. doi: 10.1371/journal.pone.0079759. eCollection 2013. PubMed PMID: 24224002; PubMed Central PMCID: PMC3818213.

Roy R, Usha V, Kermani A, Scott DJ, Hyde EI, Besra GS, Alderwick LJ, Fütterer K. Synthesis of α-glucan in mycobacteria involves a hetero-octameric complex of trehalose synthase TreS and Maltokinase Pep2. ACS Chem Biol. 2013 Oct 18;8(10):2245-55. doi: 10.1021/cb400508k. Epub 2013 Aug 13. PubMed PMID: 23901909; PubMed Central PMCID: PMC3805332.

Batt SM, Jabeen T, Bhowruth V, Quill L, Lund PA, Eggeling L, Alderwick LJ, Fütterer K, Besra GS. Structural basis of inhibition of Mycobacterium tuberculosis DprE1 by benzothiazinone inhibitors. Proc Natl Acad Sci U S A. 2012  Jul 10;109(28):11354-9. doi: 10.1073/pnas.1205735109. Epub 2012 Jun 25. PubMed PMID: 22733761; PubMed Central PMCID: PMC3396498.

Alderwick LJ, Lloyd GS, Ghadbane H, May JW, Bhatt A, Eggeling L, Fütterer K, Besra GS. The C-terminal domain of the Arabinosyltransferase Mycobacterium tuberculosis EmbC is a lectin-like carbohydrate binding module. PLoS Pathog. 2011 Feb;7(2):e1001299. doi: 10.1371/journal.ppat.1001299. Epub 2011 Feb 24. PubMed PMID: 21383969; PubMed Central PMCID: PMC3044687.

Alderwick LJ, Lloyd GS, Lloyd AJ, Lovering AL, Eggeling L, Besra GS. Biochemical characterization of the Mycobacterium tuberculosis phosphoribosyl-1-pyrophosphate synthetase. Glycobiology. 2011 Apr;21(4):410-25. doi: 10.1093/glycob/cwq173. Epub 2010 Nov 2. PubMed PMID: 21045009; PubMed Central PMCID: PMC3055594.

Birch HL, Alderwick LJ, Appelmelk BJ, Maaskant J, Bhatt A, Singh A, Nigou J,  Eggeling L, Geurtsen J, Besra GS. A truncated lipoglycan from mycobacteria with altered immunological properties. Proc Natl Acad Sci U S A. 2010 Feb 9;107(6):2634-9. doi: 10.1073/pnas.0915082107. Epub 2010 Jan 25. PubMed PMID: 20133807; PubMed Central PMCID: PMC2823879.

Birch HL, Alderwick LJ, Rittmann D, Krumbach K, Etterich H, Grzegorzewicz A,  McNeil MR, Eggeling L, Besra GS. Identification of a terminal rhamnopyranosyltransferase (RptA) involved in Corynebacterium glutamicum cell wall biosynthesis. J Bacteriol. 2009 Aug;191(15):4879-87. doi: 10.1128/JB.00296-09. Epub 2009 May 29. PubMed PMID: 19482925; PubMed Central PMCID: PMC2715713.

Bhowruth V, Alderwick LJ, Brown AK, Bhatt A, Besra GS. Tuberculosis: a balanced diet of lipids and carbohydrates. Biochem Soc Trans. 2008 Aug;36(Pt 4):555-65. doi: 10.1042/BST0360555. Review. PubMed PMID: 18631118.

Birch HL, Alderwick LJ, Bhatt A, Rittmann D, Krumbach K, Singh A, Bai Y, Lowary TL, Eggeling L, Besra GS. Biosynthesis of mycobacterial arabinogalactan: identification of a novel alpha(1-->3) arabinofuranosyltransferase. Mol Microbiol. 2008 Sep;69(5):1191-206. doi: 10.1111/j.1365-2958.2008.06354.x. Epub 2008 Jul 4. PubMed PMID: 18627460; PubMed Central PMCID: PMC2610374.

Mishra AK, Alderwick LJ, Rittmann D, Wang C, Bhatt A, Jacobs WR Jr, Takayama  K, Eggeling L, Besra GS. Identification of a novel alpha(1-->6) mannopyranosyltransferase MptB from Corynebacterium glutamicum by deletion of a conserved gene, NCgl1505, affords a lipomannan- and lipoarabinomannan-deficient mutant. Mol Microbiol. 2008 Jun;68(6):1595-613. doi: 10.1111/j.1365-2958.2008.06265.x. Epub 2008 Apr 28. PubMed PMID: 18452585; PubMed Central PMCID: PMC2440535.

Mishra AK, Klein C, Gurcha SS, Alderwick LJ, Babu P, Hitchen PG, Morris HR, Dell A, Besra GS, Eggeling L. Structural characterization and functional properties of a novel lipomannan variant isolated from a Corynebacterium glutamicum pimB' mutant. Antonie Van Leeuwenhoek. 2008 Aug;94(2):277-87. doi: 10.1007/s10482-008-9243-1. Epub 2008 Apr 18. PubMed PMID: 18421567; PubMed Central PMCID: PMC2480597.

Alderwick LJ, Dover LG, Veerapen N, Gurcha SS, Kremer L, Roper DL, Pathak AK, Reynolds RC, Besra GS. Expression, purification and characterisation of soluble GlfT and the identification of a novel galactofuranosyltransferase Rv3782 involved in priming GlfT-mediated galactan polymerisation in Mycobacterium tuberculosis. Protein Expr Purif. 2008 Apr;58(2):332-41. doi: 10.1016/j.pep.2007.11.012. Epub 2007 Dec 8. PubMed PMID: 18248822.

Molle V, Reynolds RC, Alderwick LJ, Besra GS, Cozzone AJ, Fütterer K, Kremer  L. EmbR2, a structural homologue of EmbR, inhibits the Mycobacterium tuberculosis kinase/substrate pair PknH/EmbR. Biochem J. 2008 Mar 1;410(2):309-17. PubMed PMID: 17999640.

Alderwick LJ, Birch HL, Mishra AK, Eggeling L, Besra GS. Structure, function  and biosynthesis of the Mycobacterium tuberculosis cell wall: arabinogalactan and lipoarabinomannan assembly with a view to discovering new drug targets. Biochem Soc Trans. 2007 Nov;35(Pt 5):1325-8. Review. PubMed PMID: 17956343.

Mishra AK, Alderwick LJ, Rittmann D, Tatituri RV, Nigou J, Gilleron M, Eggeling L, Besra GS. Identification of an alpha(1-->6) mannopyranosyltransferase (MptA), involved in Corynebacterium glutamicum lipomanann biosynthesis, and identification of its orthologue in Mycobacterium tuberculosis. Mol Microbiol. 2007 Sep;65(6):1503-17. Epub 2007 Aug 21. PubMed PMID: 17714444; PubMed Central PMCID: PMC2157549.

Vafiadi C, Topakas E, Alderwick LJ, Besra GS, Christakopoulos P. Chemoenzymatic synthesis of feruloyl D-arabinose as a potential anti-mycobacterial agent. Biotechnol Lett. 2007 Nov;29(11):1771-4. Epub 2007 Aug  4. PubMed PMID: 17676274.

Tatituri RV, Alderwick LJ, Mishra AK, Nigou J, Gilleron M, Krumbach K, Hitchen P, Giordano A, Morris HR, Dell A, Eggeling L, Besra GS. Structural characterization of a partially arabinosylated lipoarabinomannan variant isolated from a Corynebacterium glutamicum ubiA mutant. Microbiology. 2007 Aug;153(Pt 8):2621-9. PubMed PMID: 17660426; PubMed Central PMCID: PMC2884958.

Dover LG, Alderwick LJ, Brown AK, Futterer K, Besra GS. Regulation of cell wall synthesis and growth. Curr Mol Med. 2007 May;7(3):247-76. Review. PubMed PMID: 17504111.

Seidel M, Alderwick LJ, Birch HL, Sahm H, Eggeling L, Besra GS. Identification of a novel arabinofuranosyltransferase AftB involved in a terminal step of cell wall arabinan biosynthesis in Corynebacterianeae, such as Corynebacterium glutamicum and Mycobacterium tuberculosis. J Biol Chem. 2007 May  18;282(20):14729-40. Epub 2007 Mar 26. PubMed PMID: 17387176.

Seidel M, Alderwick LJ, Sahm H, Besra GS, Eggeling L. Topology and mutational analysis of the single Emb arabinofuranosyltransferase of Corynebacterium glutamicum as a model of Emb proteins of Mycobacterium tuberculosis. Glycobiology. 2007 Feb;17(2):210-9. Epub 2006 Nov 6. PubMed PMID: 17088267.

Alderwick LJ, Dover LG, Seidel M, Gande R, Sahm H, Eggeling L, Besra GS. Arabinan-deficient mutants of Corynebacterium glutamicum and the consequent flux  in decaprenylmonophosphoryl-D-arabinose metabolism. Glycobiology. 2006 Nov;16(11):1073-81. Epub 2006 Aug 4. PubMed PMID: 16891347.

Alderwick LJ, Seidel M, Sahm H, Besra GS, Eggeling L. Identification of a novel arabinofuranosyltransferase (AftA) involved in cell wall arabinan biosynthesis in Mycobacterium tuberculosis. J Biol Chem. 2006 Jun 9;281(23):15653-61. Epub 2006 Apr 4. PubMed PMID: 16595677.

Alderwick LJ, Molle V, Kremer L, Cozzone AJ, Dafforn TR, Besra GS, Fütterer K. Molecular structure of EmbR, a response element of Ser/Thr kinase signaling in Mycobacterium tuberculosis. Proc Natl Acad Sci U S A. 2006 Feb 21;103(8):2558-63. Epub 2006 Feb 13. PubMed PMID: 16477027; PubMed Central PMCID: PMC1413777.

Alderwick LJ, Radmacher E, Seidel M, Gande R, Hitchen PG, Morris HR, Dell A,  Sahm H, Eggeling L, Besra GS. Deletion of Cg-emb in corynebacterianeae leads to a novel truncated cell wall arabinogalactan, whereas inactivation of Cg-ubiA results in an arabinan-deficient mutant with a cell wall galactan core. J Biol Chem. 2005 Sep 16;280(37):32362-71. Epub 2005 Jul 21. PubMed PMID: 16040600.

Radmacher E, Stansen KC, Besra GS, Alderwick LJ, Maughan WN, Hollweg G, Sahm  H, Wendisch VF, Eggeling L. Ethambutol, a cell wall inhibitor of Mycobacterium tuberculosis, elicits L-glutamate efflux of Corynebacterium glutamicum. Microbiology. 2005 May;151(Pt 5):1359-68. PubMed PMID: 15870446.

Radmacher E, Alderwick LJ, Besra GS, Brown AK, Gibson KJ, Sahm H, Eggeling L. Two functional FAS-I type fatty acid synthases in Corynebacterium glutamicum. Microbiology. 2005 Jul;151(Pt 7):2421-7. PubMed PMID: 16000732.

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