Tuberculosis owes its persistence to the remarkable adaptability of Mycobacterium tuberculosis. Recent research from CSIR-Centre for Cellular and Molecular Biology, Hyderabad, has unveiled the critical roles of enzymes CysM and CysK2 in cysteine synthesis, a key process that enables Mtb to survive the host’s immune defenses, offering potential targets for innovative TB treatments.
In a race, the person in the first position can’t simply stop running, thinking they’re in the lead — at least not until the race is finished. In a hypothetical never ending race, the runner has to keep running forever. Once they stop, they fall behind. As the Red Queen said to Alice in Lewis Carroll’s Through the Looking-Glass:
…it takes all the running you can do, to keep in the same place..
Something similar happens in the evolutionary race. Every organism must evolve, not just to survive, but to thrive against ever-evolving adversaries. The moment they stop, they are left behind. In the context of evolution, that means extinction. One master that has managed to stay in the race for millennia is Mycobacterium tuberculosis (Mtb), the bacterium which causes tuberculosis (TB).
Tuberculosis is one of the deadliest diseases known to mankind. Humans, as hosts, have continuously worked to defend against it. Despite these defences, the bacterium thrives by utilising an enzymatic toolkit that enables it to withstand hostile environments.
Recent research published in eLife, led by Mehak Zahoor Khan, the first author of the study, from Vinay Nandicoori’s lab at the CSIR-Centre for Cellular and Molecular Biology, Hyderabad, reveals how this resilience may occur.
Central to this discovery are the enzymes CysM and CysK2, which catalyse cysteine synthesis, vital for the bacterium’s antioxidant defence system This neutralises harmful oxidative molecules produced by the host’s immune system. While the general functions of these enzymes were previously known, this study pinpoints the specific conditions under which they are activated. “The non-redundancy of cysteine synthesis under stress is notable,” explains Khan. “While CysK2 and CysM might seem non-essential for routine growth in-vitro, under host-induced stress, their roles become crucial as they upregulate sulphur metabolism to help the bacteria survive.”
This research reveals previously perceived redundancies in Mtb as strategic adaptations. These enzymes typically inactive, become crucial under attack, enabling the bacterium to persist within diverse human populations. Identifying how these enzymes function under certain conditions points towards novel treatments for TB, especially when the existing treatments are not effective. Nandicoori highlights,
Our study points to potential therapeutic targets within Mtb. By distinguishing the roles of CysM and CysK2, we pave the way for developing specific treatments that could be particularly effective against drug-resistant strains.
The significance of these enzymes reaches far back in the bacterium’s evolutionary history, reflecting adaptations likely shaped by long-standing battles with human immune defences. “This research reveals a unique ‘biological insulation’ in cysteine biosynthesis, with three distinct pathways shaped by convergent evolution. Such redundancy is crucial for the bacterium’s continued success in human infection,” notes Luiz Pedro S. de Carvalho, a collaborator in the study from the The Herbert Wertheim UF Scripps Institute of Biomedical Innovation and Technology. This evolutionary process demonstrates how similar traits have independently evolved in different lineages, showcasing Mtb’s remarkable ability to adapt to diverse environments.
“The redundancy in cysteine biosynthesis pathways underscores the hostile environment against which the bacteria must safeguard itself to establish infection and cause disease,” adds Dhiraj Kumar, Scientist, International Centre for Genetic Engineering and Biotechnology (ICGEB), New Delhi, who specialises in the Mtb host-pathogen interaction and is not related to the study.
Infections have always been a major force in evolution, pushing Mtb to constantly adapt and showcasing its ability to survive and evolve. As the global health community fights drug-resistant tuberculosis, insights from recent studies are crucial. They enhance our understanding of the bacteria’s survival and aid in developing more effective treatments.
Ongoing research into the bacterium’s adaptations could lead to better treatments and provide insights into other diseases, impacting public health globally.
The bacterium is never going to stop running the race. We should not either.
…If you want to get somewhere else, you must run at least twice as fast as that!