Genetic basis of antibiotic resistance in mycobacterium tuberculosis

Abstract EN

In the wake of the human immunodeficiency virus epidemic, the incidence of tuberculosis is rising rapidly.

The treatment of tuberculosis is threatened by the emergence of multidrug-resistant strains of Mycobacterium tuberculosis.

M.

tuberculosis is usually treated with only a limited number of antimicrobial agents, the most important ones being rifampin (RIF), isoniazid (INH), streptomycin (SM), and ethambutol (EMB).

Resistance to RIF is conferred by mutations resulting in at least eight amino acid substitutions in the rpoB subunit of RNA polymerase.

INH acts by inhibiting an oxygen-sensitive pathway in the mycolic acid biosynthesis of the cell wall.

At least four genes have been described to be involved in resistance to INH : the katG gene, which encodes a catalase ; the inhA gene, which is the target for INH ; and the oxyR gene and neighboring aphC gene and their intergenic region.

SM resistance has been associated with mutations in the rrs gene encoding 16S rRNA and the rspL gene encoding the S12 ribosomal protein.

EMB resistance is associated with an altered EmbB protein, a protein involved in the synthesis of the cell wall component arabinogalactan.

Because the organism is slow growing, traditional diagnosis is time-consuming.

Traditional phenotypic determination of resistance may take up to 10 weeks after referral of a sample to the laboratory, but both commercial and in-house amplification assays can greatly improve the detection time.

Therefore, it is not surprising that within the past years a multitude of different resistance assays based on molecular techniques were specifically developed for M.

tuberculosis.