Dec. 21, 2004 A new antibiotic shows promise, thus far in mice, for treating tuberculosis much faster than current drugs do, scientists report. Additional evidence indicates that the antibiotic may work against multidrug-resistant strains of the tuberculosis bug. Studies in healthy human volunteers have indicated that the drug is safe for humans to take, and further human studies are currently underway.
These findings, by Koen Andries of Johnson & Johnson Pharmaceutical Research and Development, LLC in Beerse, Belgium and colleagues, will appear online in the 9 December Science Express, part of the journal Science, published by AAAS, the nonprofit science society.
Globally, tuberculosis is second only to AIDS as a leading cause of death from infectious disease, causing approximately two million deaths per year. The tuberculosis and HIV epidemics fuel one another; at least 11 million adults are infected with both pathogens, according to the Global Alliance for TB Drug Development.
No new tuberculosis-specific drugs have been discovered in the last 40 years, and emerging strains of the bacterium that are resistant to multiple drugs are an increasingly worrisome problem. The current treatment for drug-sensitive tuberculosis recommended by the World Health Organization consists of a cocktail of drugs that must be taken for six to nine months.
"The world desperately needs a new tuberculosis drug that can combat resistant strains of the bacterium and that is easier for patients to take. The evidence thus far suggests that this new drug lead may be up to both tasks, which is encouraging news for global health," said Katrina Kelner, Deputy Editor, life sciences, at Science.
"If this drug is ultimately approved for humans, it could lead to a change in treatment paradigm for tuberculosis," Andries said.
The drug belongs to a family of compounds called "diarylquinolines," or "DARQs" recently patented by Johnson & Johnson. The research team identified this family by screening a large number of compounds from its chemical "library" to see what effects the compounds had on M. smegmatis (used as a surrogate for M. tuberculosis because it's nonpathogenic).
The most promising member of the DARQ family was a compound called R207910.
R207910 operates in a completely different way from other known antibiotics, the findings suggest. It appears to inhibit the cell's machinery for producing energy in the form of ATP molecules. Currently there are four main classes of antibiotics, those that inhibit the bacteria's cell-wall synthesis, protein synthesis, folate biosynthesis, or nucleic acid replication.
"Our compound is very different because it's the first antibiotic to my knowledge shown to be active against any bacteria by inhibiting their energy supply. The name DARQ was invented before we identified this mechanism, but you could describe what the drug does as cutting off the energy for bacteria -- turning off the lights, you could say," Andries said.
Experiments in cell cultures showed that R207910 is potent against several different mycobacteria, including drug-resistant strains of M. tuberculosis. The drug did not target other bacteria, an advantage because less selective antibiotics can generate resistance genes in other bacterial species, and may interfere with the intestinal flora.
Next, the researchers tested their compound in mice, finding that one month of treatment with a drug cocktail that included R207910 reduced the bacterial load in the lungs to the same extent than the old cocktail did after two months. After two months, the mice's lungs seemed to be completely clear of bacteria.
These findings suggest that tuberculosis therapies including the new drug might reduce the treatment time by about 50 percent.
Shortening the drug regimen could go a long way toward making the treatment more effective. Many patients currently stop taking the drugs before their infection is cleared because of the side effects and inconvenience, according to Andries.
To improve adherence to the lengthy regimen of current tuberculosis medicines, the WHO recommends that healthcare workers directly observe patients taking their medications, a practice called "DOTS," for "Directly Observed Treatment, Short Course."
"This system is very effective but puts undue strain to the healthcare system. A shorter TB drug regimen will radically improve treatment and compliance, accelerate the reach of DOTS and allow more patients to be treated," Andries said.
"Compliance is an important problem in some areas," he added. "It can be rather difficult explaining to patients that they have to continue taking those nasty drugs even months after their symptoms have disappeared."
In their Science study, the researchers also report the results of the first phase of testing the drug in humans. Like all phase I trials, the study used healthy volunteers to test the drug's safety. The study involved 81 volunteers, a portion of whom received a placebo instead of the drug.
The symptoms that researchers developed were "mild" and what researchers would normally see when testing a drug that caused no serious effects, according to Andries.
"So far the safety of this compound is really fine. Of course we caution that we have only studied a limited number of people for limited amount of time, so further research is necessary," Andries said. Phase 2 clinical trials to measure the drug's efficacy are currently underway. Phase 3 trials would compare it with standard treatments.
During the study, the drug levels in the volunteers' plasma reached levels that were about seven times higher than they were in the mice that had been successfully treated.
"Barring any unsuspected side effects we really do think we have a very interesting compound," Andries said. "Our studies indicate that the plasma levels only need to be as high as they were in mice in order to be effective, but we can also exceed those levels in humans significantly without any obvious side effects," he said.
Dr. Andries' coauthors are Peter Verhasselt, Hinrich Göhlmann, Jean-Marc Neefs, Hans Winkler, Jef Van Gestel, Philip Timmerman, and Didier de Chaffoy at Johnson & Johnson Pharmaceutical Research and Development, LLC in Beerse, Belgium; Jerome Guillemont at Johnson & Johnson Pharmaceutical Research and Development in Val de Reuil, France; Min Zhu at Johnson & Johnson Pharmaceutical Research and Development, LLC in Raritan, NJ; Ennis Lee, and Peter Williams at Johnson & Johnson Pharmaceutical Research and Development, LLC in High Wycome, UK; Emma Huitric and Sven Hoffner at Swedish Institute for Infectious Disease Control in Solna, Sweden; Emmanuelle Cambau, Chantal Truffot-Pernot, Nacer Lounis, and Vincent Jarlier at Pitié-Salpêtrière School of Medicine in Paris, France. Nacer Lounis is currently at Johns Hopkins University School of Medicine in Baltimore, MD.
The study was supported by Johnson & Johnson Pharmaceutical Research and Development, LLC, and animal work in Paris was also supported by annual grants from Association Française Raoul Follereau, INSERM and, Ministère de l'Education Nationale et de la Recherche.
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