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Antimicrobial Agents and Chemotherapy, July 1998, p. 1853-1857, Vol. 42, No. 7
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Contribution of rpoB Mutations to Development of Rifamycin Cross-Resistance in Mycobacterium tuberculosis

D. L. Williams,1,* L. Spring,1 L. Collins,1 L. P. Miller,2 L. B. Heifets,3 P. R. J. Gangadharam,4 and T. P. Gillis1

Gillis W. Long Hansen's Disease Research Laboratory, School of Veterinary Medicine, Louisiana State University, Baton Rouge, Louisiana1; University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, New Jersey2; National Jewish Medical and Research Center, Denver, Colorado3; and Mycobacteriology Research Laboratory, Section of Infectious Diseases, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois4

Received 8 December 1997/Returned for modification 18 February 1998/Accepted 6 May 1998

The contributions of 23 insertion, deletion, or missense mutations within an 81-bp fragment of rpoB, the gene encoding the beta -subunit of the DNA-dependent RNA polymerase of Mycobacterium tuberculosis, to the development of resistance to rifamycins (rifampin, rifabutin, rifapentine, and KRM-1648) in 29 rifampin-resistant clinical isolates were defined. Specific mutant rpoB alleles led to the development of cross-resistance to all rifamycins tested, while a subset of mutations were associated with resistance to rifampin and rifapentine but not to KRM-1648 or rifabutin. To further study the impact of specific rpoB mutant alleles on the development of rifamycin resistance, mutations were incorporated into the rpoB gene of M. tuberculosis H37Rv, contained on a mycobacterial shuttle plasmid, by in vitro mutagenesis. Recombinant M. tuberculosis clones containing plasmids with specific mutations in either codon 531 or 526 of rpoB exhibited high-level resistance to all rifamycins tested, whereas clones containing a plasmid with a mutation in codon 516 exhibited high-level resistance to rifampin and rifapentine but were susceptible to both rifabutin and KRM-1648. These results provided additional proof of the association of specific rpoB mutations with the development of rifamycin resistance and corroborate previous reports of the usefulness of rpoB genotyping for predicting rifamycin-resistant phenotypes.

* Corresponding author. Mailing address: Molecular Biology Research Department, Laboratory Research Branch, G.W. Long Hansen's Disease Center at School of Veterinary Medicine, Louisiana State University, P.O. Box 25072, Baton Rouge, LA 70894. Phone: (504) 346-5766. Fax: (504) 346-5786. E-mail: dwill21{at}lsu.edu.

Antimicrobial Agents and Chemotherapy, July 1998, p. 1853-1857, Vol. 42, No. 7
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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