Spry Group - Drug discovery for infectious diseases

The number of lives lost annually due to antimicrobial resistance is increasing, and by 2050, is estimated to reach 10 million [1]. New antimicrobial drugs are desperately needed to supplement a dangerously underdeveloped antimicrobial drug discovery pipeline. The Spry group focuses on validating new drug targets and identifying new drugs to combat key pathogenic microbes responsible for human disease. The primary diseases in their sights are malaria (caused by Plasmodium parasites) and tuberculosis (TB, caused by Mycobacterium tuberculosis), which claimed 0.6 and 1.5 million lives worldwide, respectively, in 2020 alone [2,3].

The Spry group use a multi-level approach to discover drug targets, specifically through learning from successful antimicrobials and uncovering microbial dependencies critical within the relevant host environment. To identify drug leads, they use strategies such as (i) drug repurposing and (ii) fragment-based drug discovery, an approach by which inhibitors are iteratively built from small chemical fragments using protein structures to guide the process [4]. They combine protein biophysics and biochemistry, structural biology, cell and molecular biology, and cellular biochemistry, to achieve a holistic understanding of drug targets and their interactions with ligands.

References: [1] Tackling drug-resistant infections globally: final report and recommendations, The Review on Antimicrobial Resistance 2016; [2] World malaria report 2021, World Health Organization; [3] Global tuberculosis report 2021, World Health Organization; [4] Nat Rev Drug Discov 2012, 51, 4990-5003.

Group Leader

Postdoctoral Fellows

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Guan, J, Spry, C, Tjhin, E et al. 2021, 'Exploring Heteroaromatic Rings as a Replacement for the Labile Amide of Antiplasmodial Pantothenamides', Journal of Medicinal Chemistry, vol. 64, pp. 4478-4497.

Evans, J, Murugesan, D, Post, J et al. 2021, 'Targeting Mycobacterium tuberculosis CoaBC through Chemical Inhibition of 4'-Phosphopantothenoyl-l-cysteine Synthetase (CoaB) Activity', ACS Infectious Diseases, vol. 7, no. 6, pp. 1666-1679.

Mendes, V, Green, S, Evans, J et al. 2021, 'Inhibiting Mycobacterium tuberculosis CoaBC by
targeting an allosteric site', Nature Communications, vol. 12.

Spry, C, Barnard, L, Kok, M et al. 2020, 'Toward a Stable and Potent Coenzyme A-Targeting Antiplasmodial Agent: Structure-Activity Relationship Studies of N-Phenethyl-α-methyl-pantothenamide', ACS Infectious Diseases, vol. 6, no. 7, pp. 1844-1854.

Spry, C & Coyne, A 2019, 'The Application of Fragment-based Approaches to the Discovery of Drugs for Neglected Tropical Diseases', in Venkatesan Jayaprakash, Daniele Castognolo, Yusuf Ozkay (ed.), Medicinal Chemistry of Neglected and Tropical Diseases: Advances in the Design and Synthesis of Antimicrobial Agents, CRC Press - Taylor & Francis Group, United States of America, pp. 18-47.

Chan, D, Hess, J, Shaw, E et al. 2019, 'Structural insights into Escherichia coli phosphopantothenoylcysteine synthetase by native ion mobility�mass spectrometry', Biochemical Journal, vol. 476, no. 0264-6021, pp. 3125 - 3139.

Spry, C, Sewell, A, Hering, Y et al 2018, 'Structure-activity analysis of CJ-15,801 analogues that interact with Plasmodium falciparum pantothenate kinase and inhibit parasite proliferation', European Journal of Medicinal Chemistry, vol. 143, pp. 1139-1147.

Tjhin, E, Spry, C, Sewell, A et al 2018, 'Mutations in the pantothenate kinase of Plasmodium falciparum confer diverse sensitivity profiles to antiplasmodial pantothenate analogues', PLoS Pathogens, vol. 14, no. 4, pp. 1-30.

Guan, J, Tjhin, E, Howieson, V et al 2018, 'Structure-Activity Relationships of Antiplasmodial Pantothenamide Analogues Reveal a New Way by Which Triazoles Mimic Amide Bonds', ChemMedChem, vol. 13, no. 24, pp. 2677-2683pp.

de Villiers, M, Spry, C, Macuamule, C et al 2017, 'Antiplasmodial Mode of Action of Pantothenamides: Pantothenate Kinase Serves as a Metabolic Activator Not as a Target', ACS Infectious Diseases, vol. 3, no. 7, pp. 527-541.

Scott, D, Spry, C & Abell, C 2016, 'Differential Scanning Fluorimetry as Part of a Biophysical Screening Cascade', in D. A. Erlanson and W. Jahnke (ed.), Fragment-based Drug Discovery: Lessons and Outlook, Wiley-VCH Verlag GmbH & Co. KGaA., Weinhem, Germany, pp. 139-172.

Spry, C & Coyne, A 2015, 'Fragment-Based Discovery of Antibacterials', in Steven Howard and Chris Abell (ed.), Fragment-Based Drug Discovery, Royal Society of Chemistry, Camridge, United Kingdom, pp. 177-196.

Saliba, K & Spry, C 2015, 'Coenzyme A Biosynthesis', in Marcel Hommel & Peter Kremsner (ed.), Encyclopedia of Malaria, Springer New York, Online, pp. 1-11pp.

Spry, C, Saliba, K & Strauss, E 2014, 'A miniaturized assay for measuring small molecule phosphorylation in the presence of complex matrices', Analytical Biochemistry, vol. 451, pp. 76-78.

Saliba, K & Spry, C 2014, 'Exploiting the coenzyme A biosynthesis pathway for the identification of new antimalarial agents: The case for pantothenamides', Biochemical Society Transactions, vol. 42, no. 4, pp. 1087-1093.

Spry, C, Macuamule, C, Lin, Z et al 2013, 'Pantothenamides Are Potent, On-Target Inhibitors of Plasmodium falciparum Growth When Serum Pantetheinase Is Inactivated', PLOS ONE (Public Library of Science), vol. 8, no. 2, pp. 1-12.

de Villiers, M, Macuamule, C, Spry, C et al 2013, 'Structural modification of pantothenamides counteracts degradation by pantetheinase and improves antiplasmodial activity', ACS Medicinal Chemistry Letters, vol. 4, no. 8, pp. 784-789.

Spry, C, Van Schalkwyk, D, Strauss, E et al 2010, 'Pantothenate Utilization by Plasmodium as a Target for Antimalarial Chemotherapy', Infectious Disorders - Drug Targets, vol. 10, no. 3, pp. 200-216.

Spry, C & Saliba, K 2009, 'The Human Malaria Parasite Plasmodium falciparum Is Not Dependent on Host Coenzyme A Biosynthesis', Journal of Biological Chemistry, vol. 284, no. 37, pp. 24904-24913.

Spry, C, Kirk, K & Saliba, K 2008, 'Coenzyme A biosynthesis: an antimicrobial drug target', FEMS Microbiology Reviews, vol. 32, pp. 56-106.

Lehane, A, Marchetti, R, Spry, C et al 2007, 'Feedback Inhibition of Pantothenate Kinase Regulates Pantothenol Uptake by the Malaria Parasite', Journal of Biological Chemistry, vol. 282, no. 35, pp. 25395-25405.

Spry, C, Chai, C, Kirk, K et al 2005, 'A Class of Pantothenic Acid Analogs Inhibits Plasmodium falciparum Pantothenate Kinase and Represses the Proliferation of Malaria Parasites', Antimicrobial Agents and Chemotherapy, vol. 49, no. 11, pp. 4649-4657.