BY MARK D. UEHLINGJanuary 15, 2008 | Scientists at Johnson & Johnson (JNJ) have announced the first novel class of antibiotics in 40 years. They will publish their work in Science early this year. The diarylquinolines, as the new compounds will be known, could offer shorter treatment regimens and be a precise weapon against tuberculosis.
DISCOVERY · JNJ's R207910 birth required help from 454 Corp., TIGR, Quintiles
JNJ scientists in Sweden, Belgium, and France began with 50 strains of tuberculosis: Thirty were harvested in the coughing, impoverished quarters of the world and were resistant to leading antibiotics. Next, in a screening campaign, a few thousand compounds were tested against TB-causing microbes. Three compounds in JNJ's chemical library turned out to be potent. The most effective, R207910, had first been unearthed in the search for drugs to use against urinary infections and immune disorders, and was dumped into JNJ compound libraries as a dud.
JNJ scientists then toiled to learn how the drug worked. JNJ sequenced four tuberculosis bacteria genomes almost in their entirety. Comparing the sequences, the scientists found two mutations in the microbial DNA. These were traced to membrane-spanning portions of an enzyme called extracellular ATP, which triggers the production of ATP synthase.
JNJ scientists discovered that R207910 inhibits ATP synthase's proton pump, which shuttles hydrogen ions across the cell membrane and constructs ATP, the universal cellular energy source. R207910 appears to bind tightly only with mycobacterial proteins — not those of other bacteria or mammals. That explains why it seems to be a potent killer of some of the most feared bacteria in hospitals, such as Streptococcus pneumoniae.
454 Corp. helped JNJ with the DNA sequencing, genome assembly, and mutation analysis. The Institute for Genomic Research (TIGR) provided a key sequence of bacterial DNA. Quintiles, the contract research organization, ran the clinical trials in London. The next step is to test the drug against active pulmonary tuberculosis.
The lead author on the Science paper, Koen Andries, said he believes the project offers neither a vindication nor an indictment of the billions spent on new drug-discovery technologies. "Traditional screening and medicinal chemistry are still working," he notes. "We didn't use genomic technology as a starting point. But it helped us identify the target. If the genome of tuberculosis hadn't been described a couple of years ago, we would not have had time to discover this."