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Research: Pathway inhibitors
Increased knowledge and understanding of the biosynthetic pathways of essential cofactors such as CoA and mycothiol, and an appreciation of how such pathways differ in different organisms, allow us to design and develop pathway inhibitors which are target one or more of the enzymes that operate in the pathway. In this manner the intracellular levels of the cofactor may be sufficiently reduced to impair the target organism’s growth, and may lead eventually lead to cell death – especially in the case of organisms that also rely on CoA to maintain their redox balance, such as Staphylococcus aureus. 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. We are also interested in selective inhibitors of the second enzyme, phosphopantothenoylcysteine synthetase (PPCS), as this selectivity may be obtained in this case due to bacterial PPCS enzymes uniquely relying on CTP for catalysis, while eukaryotic enzyme depend on ATP.
In the mycothiol pathway we are focused on MshB and MshD inhibitors, the second and fourth enzymes in the pathway respectively.
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