[log in to unmask]" type="cite">Thesis Defense Announcement
To:  The George Mason University Community

Candidate: Elizabeth McKenney
Program: Master of Science in Biology

Date:   Friday June 17, 2011
Time:   11:00 a.m.
Place:  George Mason University, Prince William campus
	     Bull Run Hall, Room 247
Thesis Chair:  Dr. Monique van Hoek

Title: "Analogs of Fosmidomycin and FR900098 as Antimicrobial Agents"


A copy of the thesis is on reserve in the Johnson Center Library, Fairfax campus.  The thesis will not be read at the meeting, but should be read in advance.

All members of the George Mason University community are invited to attend.


Isoprenoids are involved in many critical cellular functions, such as cell wall and membrane biosynthesis and electron transport.  Plants, fungi, and some bacteria use the methylerythritol phosphate (MEP) pathway to generate isoprenoids.  Since the MEP pathway is absent in animals, enzymes of this pathway are attractive targets for the development of a novel class of antibiotics.  Fosmidomycin and FR900098 are two antibiotics that are potent inhibitors of 1-deoxy-D-xylulose 5-phosphate reductoisomerase (DXR), the enzyme involved in the first committed step of the MEP pathway.  Fosmidomycin is currently in clinical trials to treat infections of Plasmodium falciparum, the organism that causes malaria.  Homologs of DXR have been identified in many bacteria, including F. tularensis, E. coli, P. aeruginosa, B. abortus, and M. tuberculosis.  Fosmidomycin inhibits the purified DXR of F. tularensis, E. coli, and M. tuberculosis. The goal of this research was to identify and test analogs of fosmidomycin and FR900098 that are more lipophilic, and therefore theoretically able to cross biological membranes more efficiently.  After screening a panel of compounds, we have identified one compound, termed EU195, which can inhibit the growth of Francisella novicida.  Fosmidomycin, FR900098, and EU195 can also inhibit the intracellular growth of F. novicida with low cytotoxicity.  These antibiotics can also prolong the survival of Galleria mellonella wax moth caterpillars that have been infected with F. novicida.  This research shows that the lipophilic FR900098 analog, EU195, may be a promising contribution to current antibiotics, and that further research in this area to improve these compounds would be beneficial.