K-RITH researchers have taken an important step forward to a better understanding of the genetic basis of drug resistant tuberculosis (TB).

Their findings, published in the journal Nature Genetics on Monday, 11 April, mark progress in the ultimate objective of identifying all possible drug resistance conferring genetic mutations in TB. This has important implications for rapid and accurate testing for drug resistance, better targeted patient treatment and antibiotic stewardship.

In KwaZulu-Natal there is a major challenge in diagnosing and treating extensively drug-resistant TB (XDR TB); strains of TB that have evolved to become resistant to not only first-line but also multiple second-line drugs. Currently the rapid molecular test in use (GeneXpert) only determines if a TB strain has a mutation which leads to resistance to the first-line drug, rifampicin. Because this rapid test is limited, many patients are needlessly put on regimens of potentially toxic second-line drugs while awaiting the results of phenotypic tests that take months because they are dependent on growing M. tuberculosis (the bacteria that causes TB). The ultimate aim to extend rapid molecular testing to second and third-line drugs can only be achieved if we can identify the mutations which cause resistance to all these drugs. Once a full list of mutations is catalogued we can use different approaches, such as genome sequencing, to identify all drug resistance conferring mutations rapidly. This will allow clinicians to tailor individual patients’ TB drug combinations for optimal treatment. This Nature Genetics article advances our knowledge about resistance at the genetic level.

K-RITH’s Dr Alex Pym and team, with collaborators from the Broad Institute, combined association and correlated evolution tests with strategies for amplifying signal from rare variants together with innovative bioinformatics to analyse the genome sequences of 498 strains of M. tuberculosis from South Africa and China. The aim of the study was to identify genes that confer novel resistance mutations that lead to second-line TB drug resistance. They were able to show that resistance to isoniazid and rifampicin and other first-line drugs could be explained by mutations that have already been identified. In contrast second-line resistance was less well explained but they could generate a list of new resistance conferring mutations. Using functional genomics they demonstrated one of these new mutations, in the gene ald (Rv2780), caused resistance to the TB drug cycloserine. Cycloserine is a standard component of drug regimens for MDR (multidrug-resistant) and XDR TB in South Africa, but has particularly harmful side effects – including severe depression.

The study shows how new bioinformatics approaches to analysing the genomes of M. tuberculosis can identify novel mechanisms of resistance. This information can be used to develop the next generation of molecular TB diagnostics that will allow for the targeted use of toxic drugs like cycloserine in only those patients who will benefit from the drug.

Read the full paper here