Professor Erick Strauss and Post Doctoral Research Assistant Anton Harmann
Strauss research group – www.researchgate.net/lab/Erick-Strauss-Lab
Research in the Strauss group is broadly focused on increasing our understanding of the enzymology of coenzyme A (CoA) and other medicinally-relevant low molecular weight thiols, and applying this knowledge in biocatalysis, and in antibiotic drug development. Our goal is to identify new drug targets in important human pathogens such as Staphylococcus aureus that exploit their dependence on these essential cofactors. Our research strategy focuses on elucidating and studying the enzymes involved in the biosynthetic pathway of the thiol-containing cofactor, and applying this knowledge in the design of inhibitors of these enzymes, and those that use the cofactor. Often such inhibitors are also analogues of the native cofactor, and can be prepared biocatalytically by co-opting the natural biosynthetic enzymes. Currently we are exploring the development of type-specific inhibitors of the first enzyme of the pathway, pantothenate kinase, which target only one of the three known types of PanK that are known to exist, and which should provide selective inhibition of bacterial PanKs in the presence of the PanK of the eukaryotic host.
Project: Targeting Staphylococcus aureus pantothenate kinase for antimicrobial drug development through fragment screening
The biosynthesis and utilisation of the central metabolic cofactor’ coenzyme A (CoA)’ have been shown to have significant potential for the development of antimicrobial targets that do not overlap with those exploited by the current arsenal of available antibiotics.(1) The value of this pathway for antimicrobial development lies in CoA being essential to several key metabolic processes such as the TCA cycle and fatty acid metabolism. In the case of Staphylococcus aureus, which does not produce glutathione, there is a strong indication that CoA also plays a role in maintaining the intracellular redox balance through the action of a unique CoA disulfide reductase enzyme.(2) The finding that the human and bacterial enzymes that are involved in CoA biosynthesis and utilisation show significant differences indicates that the development of antimicrobials with low cytotoxicity should be possible.(3, 4)
Our main goal is to develop new, targeted agents for the selective inhibition of methicillin-resistant Staphylococcus aureus (MRSA) growth. CoA is an essential metabolic cofactor required in all organisms for multiple biochemical reactions.(5) In S. aureus, CoA has been indicated to play a key additional role in redox-homeostasis: millimolar levels of CoA is produced for potential protection from oxygen toxicity, as S. aureus does not produce glutathione.(6, 7) Hence, xenobiotic disruption of CoA production and/or utilisation could be a novel strategy to combat MRSA infection.
Therefore, we hypothesise that the disruption of CoA biosynthesis and utilisation by SaPanK inhibitors and pseudosubstrates, used either individually or in combination, is a potential strategy for MRSA growth inhibition.
Crystal-based discovery of new Pan analogs as inhibitors of SaPanK with MRSA growth inhibition potential.
Inhibitor discovery will begin by crystallising the ternary SaPanK•ATP•N7Pan complex. We will make use of XChem at Diamond to screen this complex against hundreds of fragments to identify potential fragments. We will then develop new Pan analogs by linking top five selected fragments to Pan, followed by experimental evaluation such as biochemical inhibitory potency, anti-MRSA efficiency and human cytotoxicity, followed by crystallographic binding mode visualisation. Finally, the best hits will be modified to ensure pantetheinase-resistance. These results will identify specific SaPanK inhibitors selective against MRSA.
The long-term objective of this project is to develop new antimicrobial therapeutics that inhibits CoA biosynthesis and/or utilization in S. aureus.
References
- Wessel J. A. Moolman, M. de Villiers and E. Strauss, Biochemical Society Transactions, 2014, 42, 1080-1086, DOI: 10.1042/bst20140131
- R. van der Westhuyzen and E. Strauss, Journal of the American Chemical Society, 2010, 132, 12853-12855, DOI: 10.1021/ja106204m
- E. Strauss, in Comprehensive Natural Products II, Elsevier, Oxford, 2010, 351-410, DOI: 10.1016/B978-008045382-8.00141-6
- C. Spry, K. Kirk and K. J. Saliba, FEMS Microbiology Reviews, 2008, 32, 56-106, DOI: 10.1111/j.1574-6976.2007.00093.x.
- J. D. Robishaw and J. R. Neely, American Journal of Physiology-Endocrinology and Metabolism, 1985, 248, E1-E9, DOI: 10.1152/ajpendo.1985.248.1.E1
- R. Gaupp, N. Ledala and G. Somerville, Frontiers in Cellular and Infection Microbiology, 2012, 2, DOI: 10.3389/fcimb.2012.00033
- K. V. Laer, C. J. Hamilton and J. Messens, Antioxidants & Redox Signaling, 2013, 18, 1642-1653, DOI: 10.1089/ars.2012.4964
Publications
Developing Pantetheinase-Resistant Pantothenamide Antibacterials: Structural Modification Impacts on PanK Interaction and Mode of Action, L. Barnard, K. J. Mostert, W. A. L. van Otterlo and E. Strauss, ACS Infect. Dis., 2018, 4, 736-743
Discovery of Potent Pantothenamide Inhibitors of Staphylococcus aureus Pantothenate Kinase through a Minimal SAR Study: Inhibition Is Due To Trapping of the Product, S. J. Hughes, L. Barnard, K. Mottaghi, W. Tempel, T. Antoshchenko, B. Soo Hong, A. Allali-Hassani, D. Smil, M. Vedadi, E. Strauss, ACS Infect. Dis., 2016, 2, 627-641
