AAC
Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Gerum, A. B.
Right arrow Articles by Sibley, C. H.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Gerum, A. B.
Right arrow Articles by Sibley, C. H.

 Previous Article  |  Next Article 

Antimicrobial Agents and Chemotherapy, November 2002, p. 3362-3369, Vol. 46, No. 11
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.11.3362-3369.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Novel Saccharomyces cerevisiae Screen Identifies WR99210 Analogues That Inhibit Mycobacterium tuberculosis Dihydrofolate Reductase

A'Lissa B. Gerum,1 Jonathan E. Ulmer,1 David P. Jacobus,2 Norman P. Jensen,2 David R. Sherman,3 and Carol Hopkins Sibley1*

Department of Genome Sciences, University of Washington, Seattle, Washington 98195-7730,1 Jacobus Pharmaceutical Co., Inc., Princeton, New Jersey 08540,2 Department of Pathobiology, University of Washington, Seattle, Washington 98195-72383

Received 16 May 2002/ Returned for modification 21 June 2002/ Accepted 23 July 2002

The ongoing selection of multidrug-resistant strains of Mycobacterium tuberculosis has markedly reduced the effectiveness of the standard treatment regimens. Thus, there is an urgent need for new drugs that are potent inhibitors of M. tuberculosis, that exhibit favorable resistance profiles, and that are well tolerated by patients. One promising drug target for treatment of mycobacterial infections is dihydrofolate reductase (DHFR; EC 1.5.1.3), a key enzyme in folate utilization. DHFR is an important drug target in many pathogens, but it has not been exploited in the search for drugs effective against M. tuberculosis. The triazine DHFR inhibitor WR99210 has been shown to be effective against other mycobacteria. We show here that WR99210 is also a potent inhibitor of M. tuberculosis and Mycobacterium bovis BCG growth in vitro and that resistance to WR99210 occurred less frequently than resistance to either rifampin or isoniazid. Screening of drugs with M. tuberculosis cultures is slow and requires biosafety level 3 facilities and procedures. We have developed an alternative strategy: initial screening in an engineered strain of the budding yeast Saccharomyces cerevisiae that is dependent on the M. tuberculosis DHFR for its growth. Using this system, we have screened 19 compounds related to WR99210 and found that 7 of these related compounds are also potent inhibitors of the M. tuberculosis DHFR. These studies suggest that compounds of this class are excellent potential leads for further development of drugs effective against M. tuberculosis.

* Corresponding author. Mailing address: Department of Genome Sciences, Box 357730, University of Washington, Seattle, WA 98195-7730. Phone: (206) 685-9378. Fax: (206) 543-0754. E-mail: sibley{at}gs.washington.edu.

Antimicrobial Agents and Chemotherapy, November 2002, p. 3362-3369, Vol. 46, No. 11
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.11.3362-3369.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:



Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
Clin. Vaccine Immunol. Clin. Microbiol. Rev.
J. Clin. Microbiol. ALL ASM JOURNALS

Copyright © 2002 by the American Society for Microbiology. All rights reserved.