Tuberculosis is the most common cause of death due to an infectious disease worldwide. If the disease is recognized in time and treated with the right combination of antibiotics, most people recover. However, the bacteria that cause tuberculosis, Mycobacterium tuberculosis, can become resistant through changes in their DNA, so-called mutations, that make the antibiotics less effective. People with drug-resistant tuberculosis have a smaller chance of recovery and often have to undergo longer treatment with more antibiotics that also have more side effects.
To be able to rapidly detect drug-resistant tuberculosis, it is important to know which mutations cause resistance. In addition, some mutations cause higher levels of resistance than others. To be able to prescribe effective treatment to people with drug-resistant tuberculosis, we must understand the impact of resistance to each of the antibiotics in the treatment regimen on the success of the treatment, and whether a higher dose of these drugs can be used to overcome the observed resistance. In her thesis “First-line anti-tuberculosis drugs revisited”, Pauline Lempens investigated the association between DNA mutations and resistance of cultured bacilli to rifampicin and isoniazid, two of the strongest antibiotics for tuberculosis. In addition, she investigated the impact of resistance on treatment outcome and transmission of rifampicin-resistant tuberculosis (RR-TB) and tuberculosis resistant to both rifampicin and isoniazid (multidrug-resistant tuberculosis (MDR-TB)). Pauline is a PhD student at the Mycobacteriology Unit of the Institute of Tropical Medicine Antwerp and has been supervised by her promotors Prof. dr. Leen Rigouts and Prof. dr. Bouke C. de Jong and her co-promotors Dr. Conor J. Meehan and Dr. Tom Decroo.
Pauline and colleagues found that well-known mutations in the genes katG, inhA, and the inhA promoter largely predict the level of isoniazid resistance of cultured tuberculosis bacilli. The combination of inhA promoter region and katG mutations was associated with the highest-level resistance, exceeding peak level concentrations of isoniazid that can be achieved within patients even at the highest doses in clinical use. In addition, the team found that not all resistance to antibiotics used in the studied MDR-TB treatment regimen makes the regimen less successful, and that high-dose isoniazid can contribute to treatment success despite the presence of tuberculosis bacilli with low- or moderate-level resistance. In a dataset of 394 MDR-TB culture isolates from Bangladesh, gathered over 6 years, Pauline and colleagues found no difference in transmission between isolates with so-called borderline mutations in the rpoB gene and those with common rpoB mutations. Borderline rpoB mutations cause clinically relevant resistance to rifampicin, but are missed by rapid culture methods because the mutations cause low-level rifampicin resistance but also cause a relatively large fitness loss of the bacilli, leading to slower growth in culture medium. In the studied Bangladesh population, the presence of mutations that restore such fitness loss of the bacilli was associated with higher levels of transmission between patients. Lastly, Pauline and team characterised a set of 50 tuberculosis isolates that tested resistant to rifampicin in culture but had no mutations in rpoB. Of these isolates, 33 belonged to the same lineage (lineage 4.7). Several mutations in genes previously identified as potentially associated with rifampicin resistance were seen in these isolates, but require further investigation to clarify their role.
Pauline’s studies contributed to and stressed the importance of accurate detection of drug resistance in order to optimise treatment of RR/MDR-TB and minimise its transmission.Supervisors
Prof. dr. Bouke de Jong ITM)
Prof. dr. Leen Rigouts (University of Antwerp/ITM)
Dr. Conor Meehan (ITM)
Dr. Tom Decroo (ITM)
Defence: 4 - 6 pm
Reception: 6 - 8 pm
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