Researchers from St Jude Children's Research Hospital in US said the drugs increased survival of mice infected with TB and were effective against drug-resistant strains of TB. The antibiotics, called spectinamides, were created by changing the chemical structure of an existing antibiotic, spectinomycin, which does not work against TB. In multiple trials of mice with both active and chronic
TB infections, researchers found that one version of the new drug - an analog known as 1599 - was as good as or better than current TB drugs at reducing levels of the bacteria in the lungs of mice.
In addition, 1599 caused no serious side effects.
"This study demonstrates how classic antibiotics derived from natural products can be redesigned to create semi-synthetic compounds to overcome drug resistance," said corresponding author Richard Lee, a member of the St Jude Department of Chemical Biology and Therapeutics. The new class of antibiotics works against TB by disrupting the function of a part of the cell known as the ribosome, which is responsible for protein synthesis. To do that, the spectinamides bind to a particular site on ribosomes that is not shared by other TB drugs. That allows the drug to be used in combination with other medications.
For this study, researchers used an approach called structure-based design to re-engineer how spectinomycin binds to the ribosome.
To guide their design efforts, scientists used a 3-D model that provided an atomic-level view of spectinomycin bound to the tuberculosis ribosome.
The research reported on the first 20 of the more than 120 spectinomycin derivatives that have resulted from the effort. The list includes 1599 and two other analogs tested
against TB in mice, researchers said.
The three analogs not only bound the ribosome tightly, but they were more successful at avoiding a TB resistance mechanism called efflux.
The TB bacteria use efflux pumps as a strategy to remove drugs and other threats from the cell before they can work against the bacteria. Efflux pumps, however, did not protect TB against spectinamides, researchers said.
The drugs were also effective against multi-drug-resistant strains of TB growing in the laboratory. The strains had been isolated from patients with the disease.
The study is published in the journal Nature Medicine.