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Journal of Bacteriology, February 2008, p. 1329-1334, Vol. 190, No. 4
0021-9193/08/$08.00+0     doi:10.1128/JB.01465-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

A Point Mutation in the Two-Component Regulator PhoP-PhoR Accounts for the Absence of Polyketide-Derived Acyltrehaloses but Not That of Phthiocerol Dimycocerosates in Mycobacterium tuberculosis H37Ra{triangledown} ,§

Marie-Laure Chesne-Seck,1,{dagger} Nathalie Barilone,2,{dagger} Frédéric Boudou,2 Jesús Gonzalo Asensio,4 Pappachan E. Kolattukudy,5 Carlos Martín,4 Stewart T. Cole,3 Brigitte Gicquel,2 Deshmukh N. Gopaul,1 and Mary Jackson2*

Laboratoire de Biochimie et Biophysique des Macromolécules—URA2185 CNRS,1 Unité de Génétique Mycobactérienne,2 Unité de Génétique Moléculaire Bactérienne, Institut Pasteur, Paris, France,3 Departamento de Microbiología, Medicina Preventiva y Salud Pública, Universidad de Zaragoza, C/Domingo Miral sn., 50009 Zaragoza, Spain,4 Department of Molecular Biology and Microbiology, University of Central Florida, Orlando, Florida 32816-23605

Received 10 September 2007/ Accepted 25 November 2007

Similarities between Mycobacterium tuberculosis phoP-phoR mutants and the attenuated laboratory strain M. tuberculosis H37Ra in terms of morphological and cytochemical properties, lipid content, gene expression and virulence attenuation prompted us to analyze the functionality of this two-component regulator in the latter strain. Sequence analysis revealed a base substitution resulting in a one-amino-acid change in the likely DNA-binding region of PhoP in H37Ra relative to H37Rv. Using gel-shift assays, we show that this mutation abrogates the ability of the H37Ra PhoP protein to bind to a 40-bp segment of its own promoter. Consistent with this result, the phoP gene from H37Rv but not that from H37Ra was able to restore the synthesis of sulfolipids, diacyltrehaloses and polyacyltrehaloses in an isogenic phoP-phoR knock-out mutant of M. tuberculosis Moreover, complementation of H37Ra with phoP from H37Rv fully restored sulfolipid, diacyltrehalose and polyacyltrehalose synthesis, clearly indicating that the lack of production of these lipids in H37Ra is solely due to the point mutation in phoP. Using a pks2-3/4 knock-out mutant of M. tuberculosis H37Rv, evidence is further provided that the above-mentioned polyketide-derived acyltrehaloses do not significantly contribute to the virulence of the tubercle bacillus in a mouse model of infection. Reasons for the attenuation of H37Ra thus most likely stand in other virulence factors, many of which are expected to belong to the PhoP regulon and another of which, unrelated to PhoP, appears to be the lack of production of phthiocerol dimycocerosates in this strain.

* Corresponding author. Mailing address: Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO 80523-1682. Phone: (970) 491-3582. Fax: (970) 491-1815. E-mail: Mary.Jackson{at}colostate.edu

{triangledown} Published ahead of print on 7 December 2007.

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

{dagger} These authors contributed equally to this work.

Journal of Bacteriology, February 2008, p. 1329-1334, Vol. 190, No. 4
0021-9193/08/$08.00+0     doi:10.1128/JB.01465-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Gupta, S., Pathak, A., Sinha, A., Sarkar, D. (2009). Mycobacterium tuberculosis PhoP Recognizes Two Adjacent Direct-Repeat Sequences To Form Head-to-Head Dimers. J. Bacteriol. 191: 7466-7476 [Abstract] [Full Text]  
  • Hatzios, S. K., Schelle, M. W., Holsclaw, C. M., Behrens, C. R., Botyanszki, Z., Lin, F. L., Carlson, B. L., Kumar, P., Leary, J. A., Bertozzi, C. R. (2009). PapA3 Is an Acyltransferase Required for Polyacyltrehalose Biosynthesis in Mycobacterium tuberculosis. J. Biol. Chem. 284: 12745-12751 [Abstract] [Full Text]  
  • Gonzalo-Asensio, J., Soto, C. Y., Arbues, A., Sancho, J., del Carmen Menendez, M., Garcia, M. J., Gicquel, B., Martin, C. (2008). The Mycobacterium tuberculosis phoPR Operon Is Positively Autoregulated in the Virulent Strain H37Rv. J. Bacteriol. 190: 7068-7078 [Abstract] [Full Text]  


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