Department Affiliation: Primary: Pharmacology and Molecular Sciences
Degree: Ph.D., University of Rochester
Rank: Assistant Professor
Telephone Number: 410-502-4807
Fax Number: 410-955-3023
E-mail address: cmeyers8@jhmi.edu
School of Medicine Address: 307-A Wood Basic Science Building, 725 N. Wolfe St., Baltimore, MD 21205
Organic and medicinal chemistry, chemical biology: drug delivery mechanisms and prodrug strategies; study of bacterial isoprenoid biosynthesis; combinatorial biosynthesis; development of potential therapeutic agents
The continued widespread exposure of bacteria to antibiotics fosters the inevitable evolution of resistance mechanisms in clinically relevant pathogens, and the emergence of antibiotic resistance in bacteria that cause life-threatening infections has occurred at an alarming rate in almost every major class of antibiotics. The fight against rapid progression of clinical resistance to antibiotics demands the sustained discovery and development of new antibiotics and exploration of novel antibacterial targets. Our long term goal is to develop novel approaches to kill pathogenic bacteria with the ultimate objective of developing potential therapeutic agents. Our strategies for creating new antibacterial agents involve interdisciplinary research in the continuum of organic, biological and medicinal chemistry. Molecular biology, protein expression and biochemistry, and synthetic chemistry are key tools for our research.
Design and synthesis of novel antibiotic prodrugs.
A prodrug is a pharmacologically inactive compound that is converted to an active drug via a biological activation process that ideally takes place at the site of action. Several reasons exist for the utilization of prodrug strategies in drug design including improvement of solubility, absorption and distribution, site specificity, metabolic or chemical instability of the parent drug, prolonged release, toxicity, poor patient acceptability and problems with formulation. Despite the success of prodrug strategies with cancer treatment, few examples are documented of the use of prodrug approaches for the treatment of bacterial infections, although a prodrug strategy could potentially be very useful to improve efficacy of known antibiotics. Our goal is to develop antibiotic prodrug approaches aimed at the revival of clinically useful antibiotics for which resistance in the most serious pathogenic bacteria is already documented. In parallel, we are interested in developing antibiotic prodrug approaches for the delivery of drugs that exhibit potent antibiotic activity but exhibit problems of low solubility, poor pharmacokinetics and toxicity. Our laboratory is designing antibiotic prodrugs that will undergo activation to liberate multiple drug molecules aimed at multiple bacterial targets simultaneously within a single bacterial cell.
Isoprenoid biosynthesis in prokaryotes.
Terpenes are a large and structurally varied class of natural products whose diverse applications range from medicinal to culinary uses. Terpene assembly in both eukaryotes and prokaryotes relies upon two basic precursors, dimethylallyl pyrophosphate (DMAPP) and isopentenyl pyrophosphate (IPP). Until recently, it was thought that the sole source of these precursors was the mevalonate pathway. However, a second isoprenoid biosynthetic pathway proceeding via non-mevalonate intermediates was recently revealed in plants and bacteria and is a potential new source of targets for the design and discovery of antibacterial, antifungal and antimalarial agents. We are interested in studying this biosynthetic pathway in an effort to identify inhibitors of isoprenoid biosynthesis in bacteria and parasites.
Representative Publications:
- Freel Meyers, C.L., Hong, L., Joswig, C. and Borch R.F. Synthesis and biological activity of novel 5-fluoro-2'-deoxyuridine phosphoramidate prodrugs, J. Med. Chem., 43:4313-4318, 2000. Pub Med Reference
- Freel Meyers, C.L. and Borch, R.F. Activation mechanisms of nucleoside phosphoramidate prodrugs, J. Med. Chem., 43:4319-4327, 2000. Pub Med Reference
- Freel Meyers, C.L. and Borch R.F. A novel method for the preparation of nucleoside diphosphates, Org. Lett., 3:3765-3768, 2001. Pub Med Reference
- Freel Meyers, C.L., Oberthür, M., Anderson, J.W., Kahne, D., and Walsh, C.T. Initial characterization of novobiocic acid noviosyl transferase activity of NovM in biosynthesis of the antibiotic novobiocin. Biochemistry, 42:4179-89, 2003. Pub Med Reference
- Freel Meyers, C.L., Oberthür, M., Xu, H., Heide, L., Kahne, D., and Walsh, C.T. Characterization of NovP and NovN: Completion of novobiocin biosynthesis by sequential tailoring of the noviosyl ring, Angew. Chem. Int. Ed. Engl., 43:67-70, 2004. Pub Med Reference
- Freel Meyers, C.L., Oberthür, M., Heide, L., Kahne, D., and Walsh, C. T. Assembly of dimeric variants of coumermycins by tandem action of the four biosynthetic enzymes CouL, CouM, CouP and NovN, Biochemistry, 43:15022-15036, 2004. Pub Med Reference
Other graduate programs in which Dr. Meyers participates:
BCMB Program
Anti-Cancer Drug Development Program
Chemistry-Biology Interface Program
