Streptococcus pneumonia (SP)takes the lives of nearly 4000 people daily, the majority of whom are children below the age of five. The organism's ability to evolve resistance mechanisms has produced strains capable of tolerating our """"""""last line of defense"""""""" antibiotics. This laboratory recently discovered that diphosphomevalonate (DPM), an intermediate in the mevalonate pathway, is a potent allosteric inhibitor of the SP mevalonate kinase (MK), and that it does not inhibit the human isozyme. The mevalonate pathway is essential for survival of the organism in mouse lung. DPM and the allosteric site offer a lead compound and target that provide an opportunity to develop a new class of antibiotics that could help eradicate this disease. Our preliminary data demonstrate that compounds based on these principles are capable of killing infectious SP in rich media. This proposal integrates structure, function and synthesis in a project designed to explore and define the three enzymes that comprise the mevalonate pathway in SP, and,in so doing, provide a basis for the design and synthesis of antibiotics. The information that this program will create is of considerable fundamental scientific value. Each of the three enzymes that comprise the pathway is a member of the GHMP kinase protein superfamily, whose biomedical relevance extends to both orphan diseases and cataract formation. We have determined the structure of MK from SP, and the structure of the DPM-inhibited complex with bound substrates is imminent. These structures define the MK-target and will reveal how DPM binding disrupts chemistry. We've also determined the structure of a ternary complex of phosphomevalonate kinase (PMK)from SP, which raises intriguing mechanistic issues that emphasize both the unique and familial structural elements of PMK. Diphosphomevalonate decaboxylase (DPM-DC) is a fascinating enzyme that decarboxylates DPM via a carbocationic transition-state. We will explore the DPM-DC mechanism by defining its transition-state structures and monitoring the formation of ligand and intermediate complexes to create an advanced catalytic paradigm for this mechanistic class.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-BCMB-B (02))
Program Officer
Khambaty, Farukh M
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Albert Einstein College of Medicine
Schools of Medicine
United States
Zip Code
Kang, Soosung; Watanabe, Mizuki; Jacobs, J C et al. (2015) Synthesis of mevalonate- and fluorinated mevalonate prodrugs and their in vitro human plasma stability. Eur J Med Chem 90:448-61
Rodriguez, Sofia B; Leyh, Thomas S (2014) An enzymatic platform for the synthesis of isoprenoid precursors. PLoS One 9:e105594
Reuther, Guido; Harris, Richard; Girvin, Mark et al. (2011) Backbone 1H, 13C, 15N NMR assignments of the unliganded and substrate ternary complex forms of mevalonate diphosphate decarboxylase from Streptococcus pneumoniae. Biomol NMR Assign 5:11-4
Lefurgy, Scott T; Rodriguez, Sofia B; Park, Chan Sun et al. (2010) Probing ligand-binding pockets of the mevalonate pathway enzymes from Streptococcus pneumoniae. J Biol Chem 285:20654-63
Kudoh, Takashi; Park, Chan Sun; Lefurgy, Scott T et al. (2010) Mevalonate analogues as substrates of enzymes in the isoprenoid biosynthetic pathway of Streptococcus pneumoniae. Bioorg Med Chem 18:1124-34
Andreassi 2nd, John L; Vetting, Matthew W; Bilder, Patrick W et al. (2009) Structure of the ternary complex of phosphomevalonate kinase: the enzyme and its family. Biochemistry 48:6461-8
Andreassi 2nd, John L; Bilder, Patrick W; Vetting, Matthew W et al. (2007) Crystal structure of the Streptococcus pneumoniae mevalonate kinase in complex with diphosphomevalonate. Protein Sci 16:983-9