With TB being such a multi-faceted disease, what aspect does your research focus on?
My research is focused on understanding how Mycobacterium tuberculosis (M. tuberculosis) evolves to evade antibiotic killing in clinical settings. M. tuberculosis, as a population, has been exposed to antibiotics for almost 80 years, but only a small percentage (less than 10%) of the global M. tuberculosis strains have clinically defined drug resistance. For the majority of the M. tuberculosis population (>90%), it is unknown whether they have evolved other mechanisms to survive antibiotic treatment beyond the conventional drug resistance. To address this knowledge gap, my research employs bacterial population genomics to investigate the evolution of M. tuberculosis in the real world and identify genes that the bacteria is mutating to increase its fitness during antibiotic treatment.
In my recent paper published in Science in December 2022, we analyzed over 50,000 genome sequences of M. tuberculosis clinical isolates and identified genes that are subjected to positive (adaptive) selection in the population. Our study revealed that one gene of M. tuberculosis, resR, was frequently mutating in clinical isolates. Although resR mutants do not cause conventional drug resistance, they do enable the bacteria to recover faster after antibiotic treatment. This phenomenon, which we now refer to as antibiotic resilience, was found to be significantly associated with treatment failure in TB patients. We also found that in TB high-burden countries such as India and China, the prevalence of resilience mutants has increased to above 10%.
The discovery of antibiotic resilience highlights the importance of under-appreciated resistance mechanisms in determining treatment outcomes and underscores the need for further studies to optimize TB diagnosis and therapeutics. By identifying these novel mechanisms of antibiotic resistance, we hope to improve our understanding of TB evolution and ultimately, help combat the global burden of TB.
What’s your favorite part of studying TB?
Tuberculosis (TB) is an age-old infectious disease that has afflicted the human population for at least 6,000 years. Despite significant advancements in medical research, TB continues to be the primary cause of human mortality attributed to a single infectious agent.
One of the most intriguing aspects of studying TB is the vast array of strategies employed by M. tuberculosis to evade both our immune system and antibiotic treatments, the mechanisms of which remain largely unknown. Therefore, delving into the evolutionary history of M. tuberculosis could prove crucial in deciphering how it adapts to overcome these challenges, thus enabling us to develop more precise interventions to combat this lethal disease.
