There is a critical need to discover new anti-infective agents to treat bacterial infections. The methylerythritol phosphate (MEP) pathway is essential to the survival of most forms of bacteria. The MEP pathway consists of seven enzymes. The fifth enzyme in the pathway is IspF (methylerythritol cyclodiphosphate synthase) and the active site for this enzyme is highly similar among different species of Gram negative bacteria. Small drug-like molecules that inhibit the IspF enzyme may lead to a new class of antibiotics. Potent inhibitors have yet to be identified for the bacterial IspF enzyme. The MEP pathway is absent in humans, which provides an opportunity for novel enzyme inhibitor development leading to antibacterial agents with reduced potential for toxicity in humans. Our long-term goal is to synthesize potent inhibitors of MEP pathway enzymes to validate which enzymes in the pathway will be most effective as targets for small molecule antimicrobial agents. The objective of this application is to identify potent small molecule inhibitors of the MEP pathway IspF enzyme, which are potent and drug-like leads so that they can be used as tool compounds, In this proposal, we will advance hit molecules that were discovered by fragment screening into lead compounds that can be used as tools to validate MEP pathway inhibition as a mechanism for new antibacterial agents. To accomplish this goal we will use structural biology and principles of modern medicinal chemistry to design and synthesize new compounds. We will assay the compounds against the IspF enzyme to assess their potency and guide the synthesis of new and even more potent compounds. The newly synthesized compounds will be assayed for their antibacterial efficacy. Compounds that display antibiotic efficacy will be further assaye to determine that they are actually inhibiting the IspF enzyme in cells by monitoring the product of the IspF enzyme. In addition the downstream products of the MEP pathway, vitamin K2 and coenzyme Q will be monitored to confirm the mechanism of action and validate that inhibition of the IspF enzyme is a could lead to a new class of antibiotics. This research is interdisciplinary i nature and will involve both graduate and undergraduate students at NIU and strengthen their educational experience as well as enhance the research experience at NIU.
The development of multi-drug resistance in bacteria that cause human disease is a growing problem in world health. The research proposed here makes use of a unique enzyme pathway that is only found in certain types of infectious disease agents, but not in human beings, to design compounds that may lead to improved drugs and other treatments for infectious diseases.