Genetics and pulmonary medicine. 5. Genetics of drug resistant tuberculosis.

Abstract

The emergence of multidrug-resistant tuberculosis (MDR-TB), generally defined as resistance to at least isoniazid and rifampicin, has generated concern for the future of tuberculosis control.1 The global magnitude of the problem is not well known. Most of the available studies are non-representative surveys of a population or a country, frequently failing to discriminate between primary and acquired resistance. However, emerging data (fig 1) suggest that, while multidrug resistance may not be a widespread problem, it remains a public health threat in areas with a high prevalence of tuberculosis and suboptimal tuberculosis control programmes.2 Progress in understanding of the basis of drug action and resistance is the key to development of diagnostic strategies, novel drugs and treatment programmes, and to gaining insight into the pathogenicity of drug resistant strains. Figure 1 Global rates of drug-resistant tuberculosis. Median, upper and lower range values reported in various studies are shown. For each drug primary (P) and acquired (A) resistance values are presented separately. WHO-IUATLD Global Surveillance Program 1985–1994.1 Bacteria use a number of strategies to achieve drug resistance. These can be roughly summarised into three categories: (1) barrier mechanisms (decreased permeability and efflux pumps); (2) degrading or inactivating enzymes—for example, β-lactamases; and (3) drug target modifications—for example, single mutation in a key gene. The genetic information for such properties may be acquired via exogenous mobile genetic elements such as plasmids or transposons, or it may reside in the chromosome. Mycobacteria are not basically different from many other bacteria in that they use several of these strategies. Firstly, mycobacteria are characterised by a specialised cell wall which displays significantly reduced permeability to many compounds.3 Secondly, mycobacteria produce degrading enzymes such as β-lactamases4 and other drug-modifying enzymes. These are among the factors cited to explain the natural resistance of many mycobacterial species …