Whipple's disease, genomics, and drug therapy
The recent articles concerning the release of the genome for Tropheryma whipplei [1, 2], the causative agent of Whipple's disease, anticipate new medical discoveries and conclusions that will be drawn from the decoding of the genome. Although the reports mention that genes for key metabolic processes were missing, we were nevertheless surprised to find that the genome does not contain the coding sequence for dihydrofolate reductase (DHFR). This is significant because competitive inhibition of DHFR by trimethoprim is the mode of action of this antibacterial agent. Lacking an adequate population for clinical studies, retrospective analyses and patient series ([3, 4] references therein) have concluded that the drug combination of trimethoprim and sulfamethoxazole are the preferred treatment regimes. The treatment goal is to disrupt purine and pyrimidine synthesis, and hence replication, by shutting down tetrahydrofolate biosynthesis. However, while the use of trimethoprim will affect the host, thereby indirectly affect the bacterium through a reduced tetrahydorfolate pool, it is unlikely that trimethoprim has any effect on tetrahydrofolate production in T. whipplei. To be sure that there weren't any weak homologues to DHFR or that the DHFR gene was somehow missed due to being part of a multi-functional enzyme, we performed a sequence search (TBLASTN) of the T. whipplei genome using the DHFR protein sequence from the fellow actinomycete, Mycobaterium tuberculosis, as the target sequence. No close or distant homologues were found. While some bacterial plasmids code for a type II DHFR that has no homology to the more common type I DHFR found in most species, type II DHFR does not bind trimethoprim and tetrahydrofolate production is unaffected by the presence of trimethoprim. Furthermore, the genome additionally lacks a gene for thymidylate synthetase, another key enzyme in the folate-one carbon pathway that utilizes the DHFR product tetrahydrofolate. Lacking randomized double-blind trials of various antibiotic regimes, the scientific study of T. whipplei and its genome is increasingly important for the development of an effective therapy.
- Research Organization:
- Pacific Northwest National Lab. (PNNL), Richland, WA (United States)
- Sponsoring Organization:
- USDOE
- DOE Contract Number:
- AC05-76RL01830
- OSTI ID:
- 15010285
- Report Number(s):
- PNWD-SA-6165; KP1102010
- Journal Information:
- The Lancet, 361(9372):1961, Journal Name: The Lancet, 361(9372):1961
- Country of Publication:
- United States
- Language:
- English
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