Genome-wide analysis of multidrug-resistant, and extensively drug-resistant, Mycobacterium tuberculosis

The appearance of drug-resistant bacteria is just another example of evolution going on, which is happening every day. The organism senses environmental adversity (e.g. an antibiotic that is killing off everyone around them), so its response is to change its genotype to SURVIVE. It’s just one more case of gene-environment interactions. The emergence and spread of Mycobacterium tuberculosis resistant to multiple anti-tuberculosis drugs is the topic of the attached report –– in which not only genetic alterations are responsible for drug resistance but also epigenetic events.

Programmatically incurable tuberculosis –– in which effective treatment regimens cannot be provided, owing to resistance to akk available drugs –– is a growing problem. Resistance to rifampicin and isoniazid is classed as multidrug-resistant tuberculosis (MDR-TB). Further resistance to the fluoroquinolones and any of the injectable drugs (amikacin, kanamycin or capreomycin) used to treat MDR-TB is termed extensively drug-resistant tuberculosis (XDR-TB).

Treatment of XDR-TB patients is prolonged and expensive; outcomes are often undesirable. The drugs used are toxic and poorly tolerated. Adverse reactions are common and may be severe and irreversible. Inadequate treatment also risks amplification of resistance to further drugs (i.e. evolution continues to occur) and may prolong opportunities for transmission. M. tuberculosis has a genome of 4.4 Mb (Mb = million bases of DNA) with a low mutation rate and no evidence of between-strain recombination or horizontal gene transfer [also called “lateral gene transfer”, this represents movement of genetic material between organisms (even other species), in contrast to the usual “vertical gene transmission of DNA from parent to offspring]. Resistance in M. tuberculosis happens principally by nucleotide alterations (DNA single-base changes or insertions or deletions) in genes encoding drug targets, drug-metabolizing enzymes, and efflux pump regulation.

Authors [see attached report] performed a genome-wide association study (GWAS) of 6,465 M. tuberculosis clinical isolates from more than 30 countries. This was followed by phylogenetics-based test for independent mutations. In addition to mutations in established and recently described resistance-associated genes –– new mutations were discovered for resistance to cycloserine, ethionamide and para-aminosalicylic acid. The capacity to detect mutations associated with resistance to these drugs was enhanced by including tests for insertions and deletions (indels). Novel epistatic relationships between candidate drug-resistance-associated genes were also identified. Their data also suggest the involvement of specific efflux pumps (drrA and Rv2688c) in the emergence of resistance. This study should help in designing new diagnostic tests and expediting investigations of resistance and compensatory epistatic mechanisms.
Nature Genet Feb 2o18; 50: 307–316

This entry was posted in Center for Environmental Genetics. Bookmark the permalink.