Selective killing of Klebsiella pneumoniae by 5-trifluoromethylthioribose. Chemotherapeutic exploitation of the enzyme 5-methylthioribose kinase.
5'-Deoxy-5'-methylthioadenosine (MTA), an important intermediate in methionine recycling, can be metabolized by one of two mechanisms that appear to be mutually exclusive. In human cells, MTA is degraded in one step to adenine and 5-methylthioribose 1-phosphate (MTR-1-P) via MTA phosphorylase. In contrast, certain microbes metabolize MTA in two steps: first to 5-methylthioribose (MTR) followed by conversion to MTR-1-P. The enzymes involved in this two-step conversion are MTA nucleosidase and MTR kinase. In both cases, MTR-1-P is subsequently recycled to methionine. Because MTR kinase is "unique" to microbes (it is also found in plant tissue) and since it is essential to microbial methionine salvage, we hypothesized that MTR kinase is a promising target for chemotherapeutic exploitation. We demonstrate that 5-trifluoromethylthioribose (TFMTR), a structural analog of MTR, is a potent inhibitor of the MTR kinase-containing organism Klebsiella pneumoniae. TFMTR not only inhibits the growth of K. pneumoniae in a dose-dependent manner (50% inhibition at approximately 40 nM) but also competitively inhibits MTR kinase activity (Ki approximately 7 microM). Furthermore, TFMTR is shown to be a substrate for MTR kinase (Km = 1.7 microM), suggesting that the drug could be converted to toxic products (e.g. trifluoromethionine or carbonothionic difluoride) in enzyme-containing organisms. Structural analogs of MTR represent a new class of compounds with the potential for treating diseases caused by MTR kinase-containing microorganisms.
Gianotti
A J
AJ
Department of Veterans Affairs Medical Center, Portland, Oregon 97201.
Tower
P A
PA
Sheley
J H
JH
Conte
P A
PA
Spiro
C
C
Ferro
A J
AJ
Fitchen
J H
JH
Riscoe
M K
MK
D000818:Animals; D002478:Cells, Cultured; D002850:Chromatography, Gel; D006801:Humans; D007711:Klebsiella pneumoniae / Q000187:drug effects* / Q000201:enzymology / Q000254:growth & development; D008715:Methionine / Q000378:metabolism; D051379:Mice; D010428:Pentosephosphates / Q000378:metabolism*; D010770:Phosphotransferases / Q000378:metabolism / Q000494:pharmacology*; D017853:Phosphotransferases (Alcohol Group Acceptor); D011683:Purine-Nucleoside Phosphorylase / Q000378:metabolism; D012267:Ribosemonophosphates / Q000378:metabolism* / Q000494:pharmacology; D013865:Thioglycosides / Q000494:pharmacology*
C023029:5'-methylthioribose 1-phosphate; D010428:Pentosephosphates; D012267:Ribosemonophosphates; D013865:Thioglycosides; C062472:5-trifluoromethylthioribose; D008715:Methionine; D011683:Purine-Nucleoside Phosphorylase; C021784:5'-methylthioadenosine phosphorylase; D010770:Phosphotransferases; D017853:Phosphotransferases (Alcohol Group Acceptor); C021787:5-methylthioribose kinase