Kasugamycin potentiates rifampicin and limits emergence of resistance in Mycobacterium tuberculosis by specifically decreasing mycobacterial mistranslation

A bacterium called Mycobacterium tuberculosis is responsible for nearly 98% of cases of tuberculosis, which kills more people worldwide than any other infectious disease. This is due, in part, to the time it takes to cure individuals of the disease: patients have to take antibiotics continuously for at least six months to eradicate M. tuberculosis in the body. Bacteria, like all cells, make proteins using instructions contained within their genetic code. Cell components called ribosomes are responsible for translating these instructions and assembling the new proteins. Sometimes the ribosomes produce proteins that are slightly different to what the cell’s genetic code specified. These ‘incorrect proteins’ may not work properly so it is generally thought that cells try to prevent the mistakes from happening. However, scientists have recently found that the ribosomes in M. tuberculosis often assemble incorrect proteins. The more mistakes the ribosomes let happen, the more likely the bacteria are to survive when they are exposed to rifampicin, an antibiotic which is often used to treat tuberculosis infections. This suggests that it may be possible to make antibiotics more effective against M. tuberculosis by using them alongside a second drug that decreases the number of ribosome mistakes. Chaudhuri, Li et al. investigated the effect of a drug called kasugamycin on M. tuberculosis when the bacterium is cultured in the lab, and when it infects mice. The experiments found that Kasugamycin decreased the number of incorrect proteins assembled by the M. tuberculosis bacterium. When the drug was present, rifampicin also killed M. tuberculosis cells more efficiently. Furthermore, in the mice but not the cell cultures, kasugamycin alone was able to restrict the growth of the bacteria. This implies that M. tuberculosis cells may use ribosome mistakes as a strategy to survive in humans and other hosts. When it was given with rifampicin, kasugamycin caused several unwanted side effects in the mice, including weight loss; this may mean that the drug is currently not suitable to use in humans. Further studies may be able to find safer ways to decrease ribosome mistakes in M. tuberculosis, which could speed up the treatment of tuberculosis.