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About the Authors:
David T. Fox
* E-mail: [email protected] (DTF); [email protected] (ATK)
Affiliation: Bioscience Division, Los Alamos National Laboratory, Los Alamos, New Mexico, United States of America
Emily N. Schmidt
Affiliation: Bioscience Division, Los Alamos National Laboratory, Los Alamos, New Mexico, United States of America
Hongzhao Tian
Affiliation: Bioscience Division, Los Alamos National Laboratory, Los Alamos, New Mexico, United States of America
Suraj Dhungana
Current address: Discovery and Analytical Sciences, RTI International, Research Triangle Park, North Carolina, United States of America
Affiliation: Bioscience Division, Los Alamos National Laboratory, Los Alamos, New Mexico, United States of America
Michael C. Valentine
Affiliation: Department of Biology, Northern Arizona University, Flagstaff, Arizona, United States of America
Nicole V. Warrington
Affiliation: Department of Chemistry, Northern Arizona University, Flagstaff, Arizona, United States of America
Paul D. Phillips
Affiliation: Department of Chemistry, Northern Arizona University, Flagstaff, Arizona, United States of America
Kellan B. Finney
Affiliation: Department of Chemistry, Northern Arizona University, Flagstaff, Arizona, United States of America
Emily K. Cope
Affiliation: Department of Biology, Northern Arizona University, Flagstaff, Arizona, United States of America
Jeff G. Leid
Affiliation: Department of Biology, Northern Arizona University, Flagstaff, Arizona, United States of America
Charles A. Testa
Affiliation: Echelon Biosciences, Inc, Salt Lake City, Utah, United States of America
Andrew T. Koppisch
* E-mail: [email protected] (DTF); [email protected] (ATK)
Affiliation: Department of Chemistry, Northern Arizona University, Flagstaff, Arizona, United States of America
Introduction
Fosmidomycin is an inhibitor of methylerythritol phosphate (MEP) synthase, which is the enzyme responsible for the first committed step in the biosynthesis of the isoprenoid precursors isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP) via the MEP pathway (Figure 1) [1]–[4].
[Figure omitted. See PDF.]
Figure 1. Biosynthesis of isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP).
IPP and DMAPP are formed through the mevalonate pathway (left) in mammals, fungi and plants and through the methylerythritol phosphate (MEP) pathway (right) in many bacteria, green algae, and plant chloroplasts. Fosmidomycin inhibits formation of IPP and DMAPP (and thus late stage isoprenoid compounds) through disruption of the MEP pathway.
https://doi.org/10.1371/journal.pone.0095271.g001
The MEP pathway is the sole route to isoprenoids in most bacteria, including mycobacteria, Gram-negative and Gram-positive strains, in addition to some eukaryotic parasites. Given that the enzymes responsible for the biosynthesis of isoprenoids are required for bacterial proliferation,...