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AsnB Is Involved in Natural Resistance of Mycobacterium smegmatis to Multiple Drugs

Department of Medical Genetics and Microbiology, University of Toronto, Medical Sciences Building, Room 4382, One King's College Circle, Toronto, Ontario M5S 1A8, Canada

Received 5 August 2005/ Returned for modification 29 September 2005/ Accepted 12 October 2005

Mycobacteria are naturally resistant to most common antibiotics and chemotherapeutic agents. The underlying molecular mechanisms are not fully understood. In this paper, we describe a hypersensitive mutant of Mycobacterium smegmatis, MS 2-39, which was isolated by screening for transposon insertion mutants of M. smegmatis mc²155 that exhibit increased sensitivity to rifampin, erythromycin, or novobiocin. The mutant MS 2-39 exhibited increased sensitivity to all three of the above mentioned antibiotics as well as fusidic acid, but its sensitivity to other antibiotics, including isoniazid, ethambutol, streptomycin, chloramphenicol, norfloxacin, tetracycline, and ß-lactams, remained unchanged. Uptake experiment with hydrophobic agents and cell wall lipid analysis suggest that the mutant cell wall is normal. The transposon insertion was localized within the asnB gene, which is predicted to encode a glutamine-dependent asparagine synthetase. Transformation of the mutant with wild-type asnB of mc²155 or asnB of Mycobacterium tuberculosis complemented the drug sensitivity phenotype. These results suggest that AsnB plays a role in the natural resistance of mycobacteria.