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Journal of Bacteriology, October 2005, p. 6603-6611, Vol. 187, No. 19
0021-9193/05/$08.00+0     doi:10.1128/JB.187.19.6603-6611.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

FbpA-Dependent Biosynthesis of Trehalose Dimycolate Is Required for the Intrinsic Multidrug Resistance, Cell Wall Structure, and Colonial Morphology of Mycobacterium smegmatis

Liem Nguyen,1,2 Satheesh Chinnapapagari,2 and Charles J. Thompson1,2*

Department of Microbiology and Immunology, Life Sciences Centre, University of British Columbia, 2350 Health Sciences Mall, Vancouver, British Columbia V6T 1Z3, Canada,1 Biozentrum, University of Basel, Klingelbergstrasse 50/70, CH-4056 Basel, Switzerland2

Received 18 April 2005/ Accepted 10 June 2005

Ligation of mycolic acids to structural components of the mycobacterial cell wall generates a hydrophobic, impermeable barrier that provides resistance to toxic compounds such as antibiotics. Secreted proteins FbpA, FbpB, and FbpC attach mycolic acids to arabinogalactan, generating mycolic acid methyl esters (MAME) or trehalose, generating {alpha},{alpha}'-trehalose dimycolate (TDM; also called cord factor). Our studies of Mycobacterium smegmatis showed that disruption of fbpA did not affect MAME levels but resulted in a 45% reduction of TDM. The fbpA mutant displayed increased sensitivity to both front-line tuberculosis-targeted drugs as well as other broad-spectrum antibiotics widely used for antibacterial chemotherapy. The irregular, hydrophobic surface of wild-type M. smegmatis colonies became hydrophilic and smooth in the mutant. While expression of M. smegmatis fbpA restored defects of the mutant, heterologous expression of the Mycobacterium tuberculosis fbpA gene was less effective. A single mutation in the M. smegmatis FbpA esterase domain inactivated its ability to provide antibiotic resistance. These data show that production of TDM by FbpA is essential for the intrinsic antibiotic resistance and normal colonial morphology of some mycobacteria and support the concept that FbpA-specific inhibitors, alone or in combination with other antibiotics, could provide an effective treatment to tuberculosis and other mycobacterial diseases.

* Corresponding author. Mailing address: Department of Microbiology and Immunology, Life Sciences Centre, University of British Columbia, 2350 Health Sciences Mall, Vancouver, BC, Canada V6T 1Z3. Phone: (604) 822-2501. Fax: (604) 822-6041. E-mail: charles.thompson{at}ubc.ca.

Journal of Bacteriology, October 2005, p. 6603-6611, Vol. 187, No. 19
0021-9193/05/$08.00+0     doi:10.1128/JB.187.19.6603-6611.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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