Structure-Activity Relationships of the MEPicides: N-Acyl and O-Linked Analogs of FR900098 as Inhibitors of Dxr from Mycobacterium tuberculosis and Yersinia pestis.
Despite continued research efforts, the threat of drug resistance from a variety of bacteria continues to plague clinical communities. Discovery and validation of novel biochemical targets will facilitate development of new drugs to combat these organisms. The methylerythritol phosphate (MEP) pathway to make isoprene units is a biosynthetic pathway essential to many bacteria. We and others have explored inhibitors of the MEP pathway as novel antibacterial agents. Mycobacterium tuberculosis, the causative agent of tuberculosis, and Yersinia pestis, resulting in the plague or "black death", both rely on the MEP pathway for isoprene production. 1-Deoxy-d-xylulose 5-phosphate reductoisomerase (Dxr) catalyzes the first committed step in the MEP pathway. We examined two series of Dxr inhibitors based on the parent structure of the retrohydroxamate natural product FR900098. The compounds contain either an extended N-acyl or O-linked alkyl/aryl group and are designed to act as bisubstrate inhibitors of the enzyme. While nearly all of the compounds inhibited both Mtb and Yp Dxr to some extent, compounds generally displayed more potent inhibition against the Yp homologue, with the best analogs displaying nanomolar IC50values. In bacterial growth inhibition assays, the phosphonic acids generally resulted in poor antibacterial activity, likely a reflection of inadequate permeability. Accordingly, diethyl and dipivaloyloxymethyl (POM) prodrug esters of these compounds were made. While the added lipophilicity did not enhance Yersinia activity, the compounds showed significantly improved antitubercular activities. The most potent compounds have Mtb MIC values of 3-12 μg/mL. Taken together, we have uncovered two series of analogs that potently inhibit Dxr homologues from Mtb and Yp. These inhibitors of the MEP pathway, termed MEPicides, serve as leads for future analog development.
Department of Chemistry, George Washington University , 800 22nd Street NW, Washington D.C. 20052, United States.
Géraldine
G
San Jose
Department of Chemistry, George Washington University , 800 22nd Street NW, Washington D.C. 20052, United States.
Emily R
ER
Jackson
Department of Chemistry and Biochemistry, George Mason University , 10900 University Boulevard, Manassas, Virginia 20110, United States.
Amanda
A
Haymond
Department of Chemistry and Biochemistry, George Mason University , 10900 University Boulevard, Manassas, Virginia 20110, United States.
Chinchu
C
Johny
Department of Pediatrics, Washington University School of Medicine , 660 S Euclid Avenue, St. Louis, Missouri 63110, United States.
Rachel L
RL
Edwards
Department of Chemistry, George Washington University , 800 22nd Street NW, Washington D.C. 20052, United States.
Xu
X
Wang
Department of Chemistry, George Washington University , 800 22nd Street NW, Washington D.C. 20052, United States.
R Carl
RC
Brothers
Department of Chemistry, George Washington University , 800 22nd Street NW, Washington D.C. 20052, United States.
Emma K
EK
Edelstein
Department of Pediatrics, Washington University School of Medicine , 660 S Euclid Avenue, St. Louis, Missouri 63110, United States.
Audrey R
AR
Odom
Tuberculosis Research Section, LCID, NIAID/NIH , 9000 Rockville Pike, Bethesda, Maryland 20892, United States.
Helena I
HI
Boshoff
Department of Chemistry and Biochemistry, George Mason University , 10900 University Boulevard, Manassas, Virginia 20110, United States.
Robin D
RD
Couch
Department of Chemistry, George Washington University , 800 22nd Street NW, Washington D.C. 20052, United States.
Cynthia S
CS
Dowd
D019747:Aldose-Ketose Isomerases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology*; D000995:Antitubercular Agents / Q000737:chemistry / Q000494:pharmacology; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D053898:Biosynthetic Pathways; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship; D015010:Yersinia pestis / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics / Q000378:metabolism
D000900:Anti-Bacterial Agents; D000995:Antitubercular Agents; D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; C114231:1-deoxy-D-xylulose 5-phosphate reductoisomerase; D019747:Aldose-Ketose Isomerases
MEP pathway; Mycobacterium tuberculosis; Yersinia pestis; antibiotic; phosphonate prodrug
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