Resistance to existing antimicrobials is a serious and increasing problem; we are faced with the prospect of
pan-resistant bacteria - bacteria that are resistant to all known antibiotics.
Tuberculosis is a particular problem. Nearly 9 million people contract active tuberculosis each year, and over 2 million die, with 98% of those deaths
occurring in the developing world. Worldwide it is the leading cause of death of women of child-bearing age.
It took US$1 billion to control 500 cases of multi-drug resistant tuberculosis in New York City in the early 1990's. There are presently about 75,000
active cases of multi-drug resistant tuberculosis in the prison population in Russia alone. Clearly, there is a pressing need for new tuberculosis treatments. |
AroA active site with its reaction intermediate bound.
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MurA and AroA
MurA and AroA are bacterial enzymes that are antibiotic targets, and are the enzymes known that catalyze carboxyvinyl transfer reactions.
MurA
is in peptidoglycan biosynthesis pathway, and is the target of the antibiotic fosfomycin. AroA is
in the aromatic amino acids biosynthetic pathway. It is also present in the malaria parasite, and in plants, where it is the target of the herbicide
glyphosate (the active ingredient in Roundup).
Although there are inhibitors for both enzymes, there is a pressing need for better ones. Fosfomycin often fails because of antibiotic-induced resistance, and
tuberculosis is intrinsically resistant. Glyphosate is a good herbicide, but is not an antibiotic.
Our goal is to understand the mechanisms of MurA and AroA in
atomic detail, then exploit that knowledge to design inhibitors that will be effective as antibiotics. We are studying MurA and AroA from E. coli,
and MurA from Lyme disease, which is closely related to tuberculosis MurA and is resistant to fosfomycin. |
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