Resistance of human pathogens to anti-infective agents poses a serious threat to human health and requires sustained efforts to develop new therapies. The essential methylerythritol phosphate (MEP) pathway for isoprenoid biosynthesis is widespread in human pathogens, including some of the most deadly infections caused by M. tuberculosis and P. falciparum. Several of the enzymes in this pathway catalyze unprecedented reactions, making them particularly attractive as targets for the development of selective inhibitors. Our long term goal is to understand catalysis in the MEP pathway toward the development of inhibitors targeting isoprenoid biosynthesis in pathogens. This proposal describes studies to examine three intriguing MEP pathway enzymes, IspG, DXP synthase and IspF.
Specific Aims 1 and 3 focus on mechanistic studies and inhibitor development of the enzymes that generate and utilize cyclodiphosphate intermediate, methylerythritol cyclodiphosphate (MEcPP). The goal of Specific Aim 2 is to understand catalysis of DXP synthase in C-N bond formation to generate the medicinally useful hydroxamic acid compound class. Anti-infective agents developed to target these enzymes have the potential to broadly impact the treatment of deadly infectious diseases.
Drug resistance in human pathogens is a global health concern requiring sustained efforts to develop new strategies for treatment of life threatening infections. The proposed studies examine the mechanistically intriguing essential methylerythritol phosphate pathway enzymes which are widespread in human pathogens. Mechanistic studies of these enzymes will lead to the development of new anti-infective agents.
|Afanador, Gustavo A; Guerra, Alfredo J; Swift, Russell P et al. (2017) A novel lipoate attachment enzyme is shared by Plasmodium and Chlamydia species. Mol Microbiol 106:439-451|
|Sanders, Sara; Vierling, Ryan J; Bartee, David et al. (2017) Challenges and Hallmarks of Establishing Alkylacetylphosphonates as Probes of Bacterial 1-Deoxy-d-xylulose 5-Phosphate Synthase. ACS Infect Dis 3:467-478|
|Zhou, Jieyu; Yang, Luying; DeColli, Alicia et al. (2017) Conformational dynamics of 1-deoxy-d-xylulose 5-phosphate synthase on ligand binding revealed by H/D exchange MS. Proc Natl Acad Sci U S A 114:9355-9360|
|Nemeria, Natalia S; Shome, Brateen; DeColli, Alicia A et al. (2016) Competence of Thiamin Diphosphate-Dependent Enzymes with 2'-Methoxythiamin Diphosphate Derived from Bacimethrin, a Naturally Occurring Thiamin Anti-vitamin. Biochemistry 55:1135-48|
|Armstrong, Christopher M; Meyers, David J; Imlay, Leah S et al. (2015) Resistance to the antimicrobial agent fosmidomycin and an FR900098 prodrug through mutations in the deoxyxylulose phosphate reductoisomerase gene (dxr). Antimicrob Agents Chemother 59:5511-9|
|Bartee, David; Morris, Francine; Al-Khouja, Amer et al. (2015) Hydroxybenzaldoximes Are D-GAP-Competitive Inhibitors of E. coli 1-Deoxy-D-Xylulose-5-Phosphate Synthase. Chembiochem 16:1771-81|
|Basta, Leighanne A Brammer; Patel, Hetalben; Kakalis, Lazaros et al. (2014) Defining critical residues for substrate binding to 1-deoxy-D-xylulose 5-phosphate synthase--active site substitutions stabilize the predecarboxylation intermediate C2?-lactylthiamin diphosphate. FEBS J 281:2820-2837|
|Afanador, Gustavo A; Matthews, Krista A; Bartee, David et al. (2014) Redox-dependent lipoylation of mitochondrial proteins in Plasmodium falciparum. Mol Microbiol 94:156-71|
|Smith, Jessica M; Warrington, Nicole V; Vierling, Ryan J et al. (2014) Targeting DXP synthase in human pathogens: enzyme inhibition and antimicrobial activity of butylacetylphosphonate. J Antibiot (Tokyo) 67:77-83|
|Morris, Francine; Vierling, Ryan; Boucher, Lauren et al. (2013) DXP synthase-catalyzed C-N bond formation: nitroso substrate specificity studies guide selective inhibitor design. Chembiochem 14:1309-15|
Showing the most recent 10 out of 15 publications