Resistance to isoniazid and ethionamide in Mycobacterium tuberculosis: Genes, mutations, and causalities

Tuberculosis (TB) chemotherapy started in the 1930s with the discovery by Domagk and colleagues of the anti-TB activity of sulfonamides. Since these compounds were very toxic and highly insoluble, analogs were synthesized, leading to the discovery of Tibione (thiacetazone, Fig. 1), a highly effective thiosemicarbazone against Mycobacterium tuberculosis (1, 2). In parallel, the natural product streptomycin (SM), discovered by Schatz and Waksman, showed activity against M. tuberculosis (3) and was used successfully to treat TB patients. Two new anti-TB drugs were discovered soon after: para-aminosalicylic acid (PAS) in 1946 (4) and isonicotinic acid hydrazine (isoniazid, INH) in 1952 (5, 6). Each drug had activity against M. tuberculosis; however, drug-resistant mutants emerged rapidly during clinical trials (7 - 9). To prevent drug resistance, in 1959, SM, PAS, and INH were combined to form the first successful multidrug, biphasic chemotherapy for TB (10). This combination treatment was so impressive that Selman Waksman wrote, "the ancient foe of man, known as consumption, the great white plague, tuberculosis, or by whatever other name, is on the way to being reduced to a minor ailment of man. The future appears bright indeed, and the complete eradication of the disease is in sight" (185, p. 217). Nevertheless, the treatment was long and expensive, and patients often dropped out prior to completing chemotherapy. In 1984, a new short-course treatment was established that showed improved efficacy and patient compliance; the drug regimen consisted of two months on INH, rifampicin (RIF), pyrazinamide (PZA), and ethambutol, followed by four months on INH and RIF only.