Mycobacterium tuberculosis (pink), the bacteria responsible for tuberculosis. Image Credit: NIAID (CC BY 2.0)
When a bacterium known as Mycobacterium tuberculosis infects humans, it can lead to a disease called tuberculosis – one of the leading causes of death from an infectious disease worldwide. The bacteria hide within certain cells in the body so that they are less accessible to the host’s immune system.
This approach is so successful that patients typically require long courses of antibiotics lasting many months to eliminate the bacteria. However, the emergence of drug-resistant strains of M. tuberculosis means that new methods to target the bacteria are urgently needed.
One possible target for future therapies is a system known as diisonitrile lipopeptide chalkophores, which bind to copper and import the metal into the bacterium from its surroundings. Although certain proteins in bacteria require copper to work properly, the target of the copper acquired by the chalkophores in M. tuberculosis has remained unclear.
Here, Buglino, Ozakman et al. used genetic and biochemical approaches to study why diisonitrile lipopeptide chalkophores collect copper in M. tuberculosis. The experiments showed that the chalkophores supply copper to proteins with a key role in respiration, the process by which cells make chemical energy needed for many cell activities.
When there was a shortage of copper in their surrounding environment, mutant M. tuberculosis cells lacking the chalkophores were less able to produce chemical energy and more likely to die than healthy M. tuberculosis cells. This effect was more severe if the cells were also missing an enzyme that enables the bacteria to respire without copper.
Further experiments in mice found that during a tuberculosis infection, the immune system targeted copper-containing proteins in its attempts to kill the bacteria. The mutant M. tuberculosis cells were less effective at infecting the mice, suggesting that chalkophores help the bacteria defend themselves against the host immune system.
Taken together, these findings reveal that copper-containing proteins in M. tuberculosis are a major target of the immune system. In the future, increasing our understanding of these proteins and identifying drugs that interfere with their activities may lead to new, more effective therapies for tuberculosis.
