BSc (University of Birmingham)

PhD (University of Birmingham)

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 recently appointed 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.

The successful career progression of Dr Alderwick, from undergraduate to scientific researcher and lecturer, is partly due to the excellent training and teaching he received at the School of Biosciences. As a result, he has a unique insight and appreciation of the modern day student studying at Birmingham. Dr Alderwick teaches course material in the following modules

Year 1

• Microbiology and Infectious Disease
• Physical Biochemistry
• Human Biochemisry
• Biochemistry

Year 2

• Membranes, Energy and Metabolism
  

Year 3

• Molecular Basis of Bacterial Infection

For a list of possible PhD projects offered by Dr Alderwick www.findaphd.com/search/customlink.asp?inst=birm-Biol&supersurname=Alderwick

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).

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.

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.

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. PNAS. 2012 Jul 10;109(28):11354-9. doi:10.1073/pnas.1205735109. Epub 2012 Jun 25. PMCID: PMC3396498
PMID: 22733761

Alderwick LJ, 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 Pathogens. 2011 Feb;7(2):e1001299. doi: 10.1371/journal.ppat.1001299. Epub 2011 Feb 24. PMID: 21383969

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

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 USA. 2010 Feb 9 107: 2634-2639. Epub 2010 Jan 25. PMID: 20133807

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. 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. 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 α(1→3) arabinofuranosyltransferase. Mol Microbiol. 2008 Sep;69(5):1191-206. 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. 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. 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. 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 α(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(Pt8):2621-9. PubMed PMID: 17660426.

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 8;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.