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Journal of Bacteriology, February 2009, p. 985-995, Vol. 191, No. 3
0021-9193/09/$08.00+0     doi:10.1128/JB.01409-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Function and Regulation of Class I Ribonucleotide Reductase-Encoding Genes in Mycobacteria{triangledown} ,{dagger}

Mohube B. Mowa,1 Digby F. Warner,1 Gilla Kaplan,2 Bavesh D. Kana,1* and Valerie Mizrahi1*

MRC/NHLS/WITS Molecular Mycobacteriology Research Unit, DST/NRF Centre of Excellence for Biomedical TB Research, School of Pathology, University of the Witwatersrand and the National Health Laboratory Service, Johannesburg 2000, South Africa,1 Laboratory of Mycobacterial Immunity and Pathogenesis, Public Health Research Institute, International Center for Public Health, 225 Warren Street, Newark, New Jersey 07103-35352

Received 8 October 2008/ Accepted 6 November 2008

Ribonucleotide reductases (RNRs) are crucial to all living cells, since they provide deoxyribonucleotides (dNTPs) for DNA synthesis and repair. In Mycobacterium tuberculosis, a class Ib RNR comprising nrdE- and nrdF2-encoded subunits is essential for growth in vitro. Interestingly, the genome of this obligate human pathogen also contains the nrdF1 (Rv1981c) and nrdB (Rv0233) genes, encoding an alternate class Ib RNR small (R2) subunit and a putative class Ic RNR R2 subunit, respectively. However, the role(s) of these subunits in dNTP provision during M. tuberculosis pathogenesis is unknown. In this study, we demonstrate that nrdF1 and nrdB are dispensable for the growth and survival of M. tuberculosis after exposure to various stresses in vitro and, further, that neither gene is required for growth and survival in mice. These observations argue against a specialist role for the alternate R2 subunits under the conditions tested. Through the construction of nrdR-deficient mutants of M. tuberculosis and Mycobacterium smegmatis, we establish that the genes encoding the essential class Ib RNR subunits are specifically regulated by an NrdR-type repressor. Moreover, a strain of M. smegmatis mc2155 lacking the 56-kb chromosomal region, which includes duplicates of nrdHIE and nrdF2, and a mutant retaining only one copy of nrdF2 are shown to be hypersensitive to the class I RNR inhibitor hydroxyurea as a result of depleted levels of the target. Together, our observations identify a potential vulnerability in dNTP provision in mycobacteria and thereby offer a compelling rationale for pursuing the class Ib RNR as a target for drug discovery.

* Corresponding author. Mailing address: Molecular Mycobacteriology Research Unit, National Health Laboratory Service, P.O. Box 1038, Johannesburg 2000, South Africa. Phone: 2711-4899030. Fax: 2711-4899397. E-mail for Bavesh D. Kana: bavesh.kana{at}nhls.ac.za. E-mail for Valerie Mizrahi: valerie.mizrahi{at}wits.ac.za

{triangledown} Published ahead of print on 21 November 2008.

{dagger} Supplemental material for this article may be found at http://jb.asm.org/.

Journal of Bacteriology, February 2009, p. 985-995, Vol. 191, No. 3
0021-9193/09/$08.00+0     doi:10.1128/JB.01409-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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