Microbiology Editor's Choice: Why does tuberculosis infection require such a long course of antibiotics?

Posted on June 3, 2019   by Microbiology Society

Each month, a manuscript published in our flagship journal Microbiology is chosen by a member of the Editorial Board. This month, the paper is titled 'Heterogeneity of ROS levels in antibiotic-exposed mycobacterial subpopulations confers differential susceptibility' and it was chosen by Dr Isabelle Martin-Verstraete.

Dr Isabelle Martin-Verstraete: In this interesting work, the redox state and the intracellular level of reactive oxygen species upon rifampin, isoniazid or H2O2 treatments were analyzed in two subpopulations of Mycobacterium smegmatis corresponding to short-sized and normal-sized cells. The results obtained allow us to propose that there is a possible link between antibiotic sensitivity and intra-bacterial ROS levels, which might have a real significance concerning phenotypic heterogeneity and antibiotics tolerance during chemotherapy.

 

Heterogeneity of ROS levels in antibiotic-exposed mycobacterial subpopulations confers differential susceptibility

Bacteria maintain population heterogeneity with specific subpopulations that significantly differ in their response to stress conditions. We had earlier shown the presence of two subpopulations in the in vitro cultures of Mycobacterium tuberculosis, Mycobacterium smegmatis, Mycobacterium xenopi and in the tubercle bacilli population present in the pulmonary tuberculosis patients’ sputum.

The data presented in the paper show that the two subpopulations significantly differ in their susceptibility to anti-tuberculosis antibiotics due to the remarkable difference in the generation of reactive oxygen species in the antibiotics-exposed cells. These findings may have implications in the emergence of drug-resistant bacteria in the clinical scenario.

We spoke with corresponding author Parthasarathi Ajitkumar, to find out more about their research:
What is your institution and how long have you been there?

Parthasarathi: I am based at the Indian Institute of Science, Bangalore, India, which is 110 years old and the topmost research and teaching institute in the country. It carries out research and teaching in all the disciplines in science and engineering. I have been a faculty in the Department of Microbiology and Cell Biology under the Biological Sciences Division of the Institute for the past 30 years.

What is your research area?

Parthasarathi: I study the features of the subpopulations of mycobacteria, including tubercle bacilli, that make them tolerant to anti-tuberculosis antibiotics, thereby enabling delay in their killing, and the features that enable them to generate genetic resistance to antibiotics.

What inspired you to research this topic?

Parthasarathi: When I went around the hospitals to collect clinical samples from tuberculosis patients, I realised that the majority of patients come from financially poor strata of the society. They work on daily or weekly wages and cannot afford to sit at home and take treatment for six months, as otherwise their family would starve. Thus, although the country has an active Tuberculosis Control Programme, which offers free diagnosis, medicines and treatment, the financially poor patients are not able to comply with the six-month-long treatment regimen.

This in turn generates drug-resistant bacilli. Hence our strategy is to eradicate the bacilli and prevent emergence of drug resistant strains by bringing down the treatment time from six months to a week or ten days – a challenging proposition! My hypothesis was that the bacteria might have some strategy to remain un-killed or tolerant to the antibiotics for a long time, meaning they require six months of exposure to antibiotics for elimination. Experiments testing this hypothesis brought out startling findings proving the hypothesis true! The data reported in the Microbiology paper gives strong indication of a mechanism that might be used by the bacilli to remain un-killed or tolerant to anti-tuberculosis antibiotics.

What is the most rewarding part of your research?

Parthasarathi: The hypothesis with which we started the experiments has been proved true in the study reported in the paper in Microbiology. This data point out a strategy that might be used by mycobacteria to remain un-killed by generating reactive oxygen species to come up as genetically resistant mutants against antibiotics.

What would you be doing if you weren't a scientist?

Parthasarathi: I would have been teaching microbiology to undergraduate, graduate and post-graduate students, inspiring them to take up research in microbiology for the benefit of mankind.