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Journal of Bacteriology, June 2000, p. 3331-3335, Vol. 182, No. 12
Department of Microbiology and Immunology,
The University of British Columbia, Vancouver, British Columbia V6T
1Z3, Canada
Received 27 October 1999/Accepted 31 March 2000
Multidrug-resistant strains of Mycobacterium
tuberculosis are a serious and continuing human health problem.
Such strains may contain as many as four or five different mutations,
and M. tuberculosis strains that are resistant to both
streptomycin and rifampin contain mutations in the rpsL and
rpoB genes, respectively. Coexisting mutations of this kind
in Escherichia coli have been shown to interact negatively
(S. L. Chakrabarti and L. Gorini, Proc. Natl. Acad. Sci. USA
72:2084-2087, 1975; S. L. Chakrabarti and L. Gorini, Proc. Natl.
Acad. Sci. USA 74:1157-1161, 1977). We investigated this possibility
in Mycobacterium smegmatis by analyzing the frequency and
nature of spontaneous mutants that are resistant to either streptomycin
or rifampin or to both antibiotics. Mutants resistant to streptomycin
were isolated from characterized rifampin-resistant mutants of M. smegmatis under selection either for one or for both antibiotics.
Similarly, mutants resistant to rifampin were isolated from
streptomycin-resistant strains. The second antibiotic resistance
mutation occurred at a lower frequency in both cases. Surprisingly, in
both cases a very high rate of reversion of the initial antibiotic
resistance allele was detected when single antibiotic selection was
used; the majority of strains resistant to only one antibiotic were
isolated by this process. Determinations of rates of mutation to
antibiotic resistance in M. smegmatis showed that the
frequencies were enhanced up to 104-fold during stationary
phase. If such behavior is also typical of slow-growing pathogenic
mycobacteria, these studies suggest that the generation of multiply
drug-resistant strains by successive mutations may be a more complex
genetic phenomenon than suspected.
0021-9193/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
Genetic Antagonism and Hypermutability in
Mycobacterium smegmatis
and
*
Corresponding author. Mailing address: Department of
Microbiology and Immunology, The University of British Columbia, 6174 University Blvd., Vancouver, B.C. V6T 1Z3, Canada. Phone: (604) 822-8883. Fax: (604) 822-6041. E-mail: jed{at}unixg.ubc.ca.
Present address: University of British Columbia Centre for Disease
Control, Vancouver, British Columbia V5Z 4R4, Canada.
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