Molecular Basis of Drug Resistance in Mycobacterium tuberculosis

Abstract

In this chapter we review the molecular mechanisms of drug resistance to the major first-and second-line antibiotics used to treat tuberculosis.In 2011, the World Health Organization (WHO) reported nearly 60,000 new cases of multidrugresistant tuberculosis (MDR-TB) (1), and estimates of the annual global incidence are much higher. The emergence of drug-resistant strains has made the treatment of TB complex, costly, toxic, time-intensive, and less efficacious. Design of a treatment regimen for drug-resistant TB includes the administration of first-line drugs to which the strains remain susceptible together with second-line drugs. These secondline agents are more expensive, more difficult to administer (several require intravenous administration), and are often associated with severe toxicities, including hepatic and renal dysfunction. In comparison to the 6 months required to treat drug-susceptible TB, drug-resistant TB requires a prolonged treatment duration of 18 to 24 months. These logistics constitute considerable hardships for patients as well as for overburdened public health services. Too frequently, premature discontinuation of therapy occurs, leading to treatment failure and the emergence of Mycobacterium tuberculosis strains with additional drug resistance.

Drug Susceptibility Profiling and Genetic Determinants of Drug Resistance in Mycobacterium kansasii

“…In M. tuberculosis, most of the EMB resistance-associated mutations are located in the embB gene (34). In our study, all M. kansasii types harbored M306I, G406P, and M423I amino acid substitutions, frequently described in EMB-resistant M. tuberculosis (35,36). As these alterations were found in both EMB-resistant (types I to IV and VI) and EMB-susceptible (type V) isolates, they cannot be considered specific for EMB resistance in M. kansasii.…”

New Insights in to the Intrinsic and Acquired Drug Resistance Mechanisms in Mycobacteria

“…A reduction in catalase/peroxidase activity as a result of katG mutations is the most common mechanism associated with INH resistance. Other such mechanisms involve mutations in the inhA promoter that result in overexpression of inhA , which confers low-level resistance to INH (Cohen et al, 2014). More than 80% of INH resistance cases could be explained by the two mutations of katG S315T and inhA promoter -15C-T (Torres et al, 2015).…”

“…The most common mechanism of resistance to aminoglycosides has been associated with an A1401G mutation in the rrs gene coding for 16S rRNA (Da Silva and Palomino, 2011). Unlike most other bacteria, which have multiple copies of the rrs gene, mycobacteria have a single copy of the gene (Cohen et al, 2014). Consequently, mutations in this gene are usually associated with high-level aminoglycoside resistance.…”

Towards individualised treatment of tuberculosis

“…rifampicin and mutations in rpoB, isoniazid and inhA, fluoroquinolones and gyrA/gyrB), degrading/inactivating enzymes and loss of prodrug activation (e.g. isoniazid and mutations in katG, pyrazinamide and pncA) (22,23). Upregulation of efflux pumps commonly seen in Gram-negative bacteria, has been identified in M. tuberculosis for some of the first-line drugs and for bedaquiline (24)(25)(26).…”