Scientists Create Detailed Genetic Map of Tuberculosis Bacterium That Could Help Develop New Antibiotics

Tuberculosis remains one of the world's deadliest infectious diseases, claiming more than a million lives each year. Treatment typically requires taking several antibiotics over a period of months, while drug-resistant forms of the disease may require even longer courses of therapy. The bacterium is particularly difficult to eliminate because of its robust cell wall and its ability to persist in the body for extended periods.

Researchers led by Jeremy Rock studied interactions among 762 genes essential for the pathogen's survival. To do so, they refined CRISPR interference (CRISPRi), a technology that allows scientists to reduce gene activity without cutting DNA or killing the bacterium. The researchers suppressed individual genes and pairs of genes, then compared the effects of these changes on bacterial growth.

The map helped clarify the functions of genes whose roles had previously remained unknown. Some, in particular, were found to be associated with the electron transport chain, a system involved in cellular energy production. Additional experiments confirmed their role in the functioning of a large protein complex responsible for cellular respiration.

The researchers also used the findings to identify promising drug combinations. They discovered four combinations with synergistic effects, in which the combined action of the drugs was stronger than expected. In one combination, an experimental compound enhanced the bactericidal effect of ethambutol, an antibiotic used to treat tuberculosis. The scientists also identified a drug combination in which the medications weakened each other's effects.

The authors believe the map could help systematize the search for new antibiotic targets and more effective treatment regimens, reducing the need to test numerous combinations through trial and error. The data are already available to other researchers. The next step is to investigate gene interactions under conditions that more closely resemble those in which the bacterium exists inside the human body.