Researchers Find Genetic “Heart” of Tuberculosis — A New Therapeutic Target

Scientists Identify a Genetic "Heart" That Tuberculosis Can't Live Without

Researchers led by infectious disease microbiologist Dr. Shelley Haydel at Arizona State University have identified a two-component regulatory system, PrrAB, that Mycobacterium tuberculosis depends on to manage respiration and energy production. In laboratory experiments, repressing PrrAB dramatically impaired the bacterium’s ability to carry out oxidative phosphorylation and reduced viable bacterial counts by nearly 100-fold in vitro.

How PrrAB Controls the Bacterium’s Energy Machinery

PrrAB acts like a central regulatory hub, controlling genes required for respiration and oxidative phosphorylation — the biochemical pathway that reduces oxygen to power production of adenosine triphosphate (ATP), the cell’s primary energy molecule. Using CRISPR interference (CRISPRi) to silence PrrAB shut down these pathways and produced a strong bactericidal effect against M. tuberculosis cultured in the lab.

DAT-48 Targets the Same Pathway and Shows Synergy

The team also examined Diarylthiazole-48 (DAT-48), an experimental anti‑tuberculosis compound. Their data indicate DAT-48 acts within the PrrAB-regulated pathway. Combining CRISPRi repression of PrrAB with DAT-48 increased bacterial killing beyond either approach alone. DAT-48 also enhanced the activity of existing respiratory-targeting TB drugs such as bedaquiline and telacebec, suggesting a functional link between PrrAB regulation and drug susceptibility.

"The essentiality of the PrrAB two-component system (TCS) in Mycobacterium tuberculosis positions it as a promising therapeutic target," Haydel and colleagues write in ACS Infectious Diseases, noting that DAT-48 "exhibited potent activity against M. tuberculosis and synergy with respiratory inhibitors."

Scope, Limitations, and Next Steps

Not all mycobacterial species responded identically to PrrAB suppression in the researchers’ experiments, but the effect against the tuberculosis pathogen was pronounced in vitro. These results are preclinical: they were obtained in cultured bacteria and have not yet been tested in animals or humans. The authors emphasize the need for in vivo validation, assessment of DAT-48’s safety and pharmacology, and exploration of whether PrrAB-targeted approaches can be translated into effective, safe therapies.

Why This Matters

Tuberculosis has been a leading infectious killer for millennia and remains a global public-health challenge. Discovering a genetic Achilles heel — a regulatory system the bacterium cannot easily do without — opens a promising avenue for drug development. If further studies confirm these findings in animals and clinical trials, PrrAB-directed strategies, alone or combined with compounds such as DAT-48 and existing respiratory inhibitors, could substantially improve TB treatment and help reduce disease burden worldwide.

Publication: Haydel et al., ACS Infectious Diseases (study details and data presented in the paper).