Antibacterial and antitubercular activity of fosmidomycin, FR900098, and their lipophilic analogs.
The nonmevalonate pathway (NMP) of isoprene biosynthesis is an exciting new route toward novel antibiotic development. Inhibitors against several enzymes in this pathway are currently under examination. A significant liability of many of these agents is poor cell penetration. To overcome and improve our understanding of this problem, we have synthesized a series of lipophilic, prodrug analogs of fosmidomycin and FR900098, inhibitors of the NMP enzyme Dxr. Several of these compounds show improved antibacterial activity against a panel of organisms relative to the parent compound, including activity against Mycobacterium tuberculosis (Mtb). Our results show that this strategy can be an effective way for improving whole cell activity of NMP inhibitors.
Department of Chemistry, George Washington University, Washington, DC 20052, USA.
Eugene
E
Uh
Emily R
ER
Jackson
Géraldine
G
San Jose
Marcus
M
Maddox
Robin E
RE
Lee
Richard E
RE
Lee
Helena I
HI
Boshoff
Cynthia S
CS
Dowd
D019747:Aldose-Ketose Isomerases / Q000037:antagonists & inhibitors*; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000995:Antitubercular Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001419:Bacteria / Q000187:drug effects*; D005578:Fosfomycin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D008055:Lipids / Q000737:chemistry; D015394:Molecular Structure; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors*; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D010088:Oxidoreductases / Q000037:antagonists & inhibitors*; D012995:Solubility
D000900:Anti-Bacterial Agents; D000995:Antitubercular Agents; D008055:Lipids; D009097:Multienzyme Complexes; D005578:Fosfomycin; C024640:fosmidomycin; C024639:3-(N-acetyl-N-hydroxy)aminopropylphosphonic acid; D010088:Oxidoreductases; C114231:1-deoxy-D-xylulose 5-phosphate reductoisomerase; D019747:Aldose-Ketose Isomerases