Caren L. Freel Meyers
725 N. Wolfe Street
WBSB 307B
Baltimore MD 21205
We take chemical-biology approaches to pursue new anti-infective strategies. Since 2005, my group has developed approaches to block the indispensable MEP pathway for isoprenoid biosynthesis and vitamin biosynthesis in pathogens. DXP synthase has emerged from this work as a particularly promising target in bacterial metabolism that we are rigorously investigating. We have pioneered studies to understand the mechanism underlying the unique activity of DXP synthase, and developed the first selective probes of DXP synthase that are currently enabling key advances toward the understanding this target function in the context of infection, and toward in vivo target validation. Our work on anti-infective drug targets is complemented by our research focused on developing prodrug strategies to treat and prevent infectious disease, including bacterial infection and HIV. Projects in this area focus on strategies to overcome barriers of low cell permeability of clinical agents, or chemical probes we develop to study antibacterial targets, including DXP synthase. We are also developing drug delivery strategies for the NRTI antiretroviral class, toward development of injectable or implantable sustained release antiretroviral drug regimens.
Johnston ML, Bonett EM, DeColli AA, Freel Meyers CL. Antibacterial Target DXP Synthase Catalyzes the Cleavage of d-Xylulose 5-Phosphate: a Study of Ketose Phosphate Binding and Ketol Transfer Reaction. Biochemistry. 2022 Sep 6;61(17):1810-1823. doi: 10.1021/acs.biochem.2c00274. Epub 2022 Aug 23. PMID: 35998648; PMCID: PMC9531112.
Johnston ML, Freel Meyers CL. Revealing Donor Substrate-Dependent Mechanistic Control on DXPS, an Enzyme in Bacterial Central Metabolism. Biochemistry. 2021 Mar 30;60(12):929-939. doi: 10.1021/acs.biochem.1c00019. Epub 2021 Mar 4. PMID: 33660509; PMCID: PMC8015787.
DeColli AA, Zhang X, Heflin KL, Jordan F, Freel Meyers CL. Active Site Histidines Link Conformational Dynamics with Catalysis on Anti-Infective Target 1-Deoxy-d-xylulose 5-Phosphate Synthase. Biochemistry. 2019 Dec 10;58(49):4970-4982. doi: 10.1021/acs.biochem.9b00878. Epub 2019 Nov 26. PMID: 31724401; PMCID: PMC6905430.
Hobson JJ, Al-Khouja A, Curley P, Meyers D, Flexner C, Siccardi M, Owen A, Meyers CF, Rannard SP. Semi-solid prodrug nanoparticles for long-acting delivery of water-soluble antiretroviral drugs within combination HIV therapies. Nat Commun. 2019 Mar 29;10(1):1413. doi: 10.1038/s41467-019-09354-z. PMID: 30926773; PMCID: PMC6441007.
Bartee D, Sanders S, Phillips PD, Harrison MJ, Koppisch AT, Freel Meyers CL. Enamide Prodrugs of Acetyl Phosphonate Deoxy-d-xylulose-5-phosphate Synthase Inhibitors as Potent Antibacterial Agents. ACS Infect Dis. 2019 Mar 8;5(3):406-417. doi: 10.1021/acsinfecdis.8b00307. Epub 2019 Jan 18. PMID: 30614674; PMCID: PMC6592275.
DeColli AA, Nemeria NS, Majumdar A, Gerfen GJ, Jordan F, Freel Meyers CL. Oxidative decarboxylation of pyruvate by 1-deoxy-d-xyulose 5-phosphate synthase, a central metabolic enzyme in bacteria. J Biol Chem. 2018 Jul 13;293(28):10857-10869. doi: 10.1074/jbc.RA118.001980. Epub 2018 May 21. PMID: 29784878; PMCID: PMC6052232.
Bartee D, Freel Meyers CL. Targeting the Unique Mechanism of Bacterial 1-Deoxy-d-xylulose-5-phosphate Synthase. Biochemistry. 2018 Jul 24;57(29):4349-4356. doi: 10.1021/acs.biochem.8b00548. Epub 2018 Jul 6. PMID: 29944345; PMCID: PMC6057799.
Sanders S, Vierling RJ, Bartee D, DeColli AA, Harrison MJ, Aklinski JL, Koppisch AT, Freel Meyers CL. Challenges and Hallmarks of Establishing Alkylacetylphosphonates as Probes of Bacterial 1-Deoxy-d-xylulose 5-Phosphate Synthase. ACS Infect Dis. 2017 Jul 14;3(7):467-478. doi: 10.1021/acsinfecdis.6b00168. Epub 2017 Jun 21. PMID: 28636325; PMCID: PMC5650741.
Armstrong CM, Meyers DJ, Imlay LS, Freel Meyers C, Odom AR. Resistance to the antimicrobial agent fosmidomycin and an FR900098 prodrug through mutations in the deoxyxylulose phosphate reductoisomerase gene (dxr). Antimicrob Agents Chemother. 2015 Sep;59(9):5511-9. doi: 10.1128/AAC.00602-15. Epub 2015 Jun 29. PMID: 26124156; PMCID: PMC4538460.
Webster MR, Zhao M, Rudek MA, Hann CL, Freel Meyers CL. Bisphosphonamidate clodronate prodrug exhibits potent anticancer activity in non-small-cell lung cancer cells. J Med Chem. 2011 Oct 13;54(19):6647-56. doi: 10.1021/jm200521a. Epub 2011 Sep 9. PMID: 21863853; PMCID: PMC3188694.