Investigating pathogen 4Fe-4S protein targets and cancer chemotherapies with bisphosphonate/diphosphate inhibitors

Abstract

The broad, long-term objective of this research is to develop drug leads for new antibiotics, antiparasitics, and cancer chemotherapeutics. Two main areas of focus are inhibition of the Methyl Erythritol Phosphate (MEP; non-mevalonate pathway) pathway in bacterial and parasitic human pathogens and inhibition of isoprenoid synthases in human cancers. For the development of antibacterials and antiparasitics, this research investigates the structure, function, and inhibition of the essential penultimate and ultimate enzymes of the MEP pathway, IspG (iron sulfur protein G; also known as GcpE and E-4-hydroxy-2-C-methyl-erythritol pyrophosphate synthase) and IspH (also know as LytB and E-4-hydroxy-2-C-methyl-erythritol pyrophosphate reductase), respectively. Investigation of novel cancer drugs focuses on mono- and combination therapies targeting the farnesyl pyrophosphate synthase (FPPS) and GGPPS (geranyl geranyl pyrophosphate synthase) enzymes with drugs that interact with several pathways involved in autophagy and apoptosis.