Synergistic activity of 5-trifluoromethylthioribose and inhibitors of methionine synthesis against Klebsiella pneumoniae.
5-Methylthioribose (MTR) is an intermediate in the methionine recycling pathway of organisms containing the enzyme MTR kinase. Analogs of MTR have been proposed as a new class of antimicrobial agents because of their ability to perturb the growth of MTR kinase-containing pathogens through inhibition of methionine salvage or by conversion to toxic products. One such analog, 5-trifluoromethylthioribose (TFMTR), has demonstrated potent inhibitory effects on the growth of Klebsiella pneumoniae (A. G. Gianotti, P. A. Tower, J. H. Sheley, P. A. Conte, C. Spiro, J. H. Fitchen, and M. K. Riscoe, J. Biol. Chem. 265:831-837, 1990). Although the mode of action of TFMTR has yet to be determined, it is believed that the drug is converted to the toxic products trifluoromethionine or carbonothioic difluoride via MTR kinase and the methionine recycling pathway. On the basis of this assumption, we theorized that blocking de novo methionine synthesis would increase dependence on the methionine salvage pathway and lead to an increased rate of synthesis of toxic metabolites from TFMTR. In this report, we show that three separate inhibitors of de novo methionine synthesis (1,2,4-triazole, azaserine, and propargylglycine) act synergistically with TFMTR in inhibiting the growth of K. pneumoniae.
Tower
P A
PA
Medical Research Service, Department of Veterans Affairs Medical Center, Beaverton, Oregon.
Johnson
L L
LL
Ferro
A J
AJ
Fitchen
J H
JH
Riscoe
M K
MK
D000480:Alkynes; D001377:Azaserine / Q000494:pharmacology*; D004357:Drug Synergism; D005998:Glycine / Q000031:analogs & derivatives* / Q000494:pharmacology; D007711:Klebsiella pneumoniae / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism; D008715:Methionine / Q000096:biosynthesis* / Q000494:pharmacology; D010293:Pargyline / Q000031:analogs & derivatives* / Q000494:pharmacology; D013865:Thioglycosides / Q000494:pharmacology*; D014230:Triazoles / Q000494:pharmacology*
D000480:Alkynes; D013865:Thioglycosides; D014230:Triazoles; C062472:5-trifluoromethylthioribose; C045575:1,2,4-triazole; C009055:propargylglycine; D001377:Azaserine; D010293:Pargyline; D008715:Methionine; D005998:Glycine