IMPLICATIONS OF MULTIDRUG-RESISTANCE FOR THE FUTURE OF SHORT-COURSE CHEMOTHERAPY OF TUBERCULOSIS - A MOLECULAR STUDY

Tuberculosis-control programmes are compromised by the increased frequ ency of multidrug-resistant strains of Mycobacterium tuberculosis. We used the polymerase chain reaction (PCR) and single-strand conformatio n polymorphism (SSCP) analysis techniques to establish the molecular b asis of resistance in 37 drug-resistant isolates of M tuberculosis, an d correlated these findings with clinical and antibiotic-sensitivity d ata. Resistance to isoniazid was found in 36 strains, 16 of which were also resistant to ethionamide. Of the 36 isoniazid-resistant strains, 23 had mutations in the katG gene, and 5 of these also had mutations in the inhA gene. A further 5 strains had alterations in the inhA locu s without the katG gene being mutated. Rifampicin resistance was less frequent (13 strains) and usually associated with isoniazid resistance (11 of 13 strains). Mutations in the rpoB gene were detected for all these rifampicin-resistant isolates. Mutations in the rpsL and rrs gen es, associated with streptomycin resistance, were found in 13 of 25 an d 2 of 25 streptomycin-resistant strains, respectively. The same chrom osomal mutations, or combinations of mutations, were found in strains displaying single or multidrug resistance, from cases of both primary and secondary resistance, and from patients infected with human immuno deficiency virus. Thus, multidrug resistance is not due to a novel mec hanism and tuberculosis chemotherapy is not subject to a new threat.