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Pathogenicity and Medical Microbiology |
Department of Infectious Diseases and Microbiology, Imperial College School of Medicine, St Mary’s Campus, Norfolk Place, London W2 1PG, UK1
Glaxo Wellcome Research and Development, Medicines Research Centre, Stevenage SG1 2NY, UK2
Author for correspondence: Douglas B. Young. Tel: +44 171 594 3956. Fax: +44 171 262 6299. e-mail: d.young{at}ic.ac.uk
Mycobacterium tuberculosis has innate resistance to a range of broad-spectrum antimicrobial agents. This may in part reflect the relative impermeability of the mycobacterial cell wall, but additional specific mechanisms may also be important. In the case of fosfomycin, it has been suggested that a key difference in the active site of the M. tuberculosis MurA enzyme might confer resistance. In Escherichia coli, fosfomycin covalently binds to a cysteine normally involved in the enzymic activity, while protein alignments predict an aspartate at this position in the M. tuberculosis MurA. In the present study, it is demonstrated that the wild-type M. tuberculosis MurA is indeed resistant to fosfomycin, and that it becomes sensitive following replacement of the aspartate residue in position 117 by a cysteine. In addition, the study illustrates the use of an inducible expression system in mycobacteria to allow functional characterization of an M. tuberculosis enzyme that is unstable during constitutive expression.
Keywords: acetamidase, fosfomycin, MurA, mycobacteria, tuberculosis
The EMBL accession number for the sequence in this paper is X96711.
a Present address: Research Division, Innogenetics NV, 9052 Ghent, Belgium.
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