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13/08/2008
Long dormant, antibiotic pipeline flowing again with more than 120 compounds in development

After years of concern about the dearth of new bacteria-fighting drugs, researchers are investigating a greater number of novel compounds than ever before.

By Victoria Stagg Elliott

In the war against drug-resistant bacteria, physicians finally might start getting some new weapons.

Experts have long complained that the lack of new antibiotics in development or ready for market, combined with the presence of increasingly resistant bacteria, has been exhausting treatment options. There are early signs, however, that this situation may be improving.

"This is a very exciting time. It's very encouraging that it appears that the pharmaceutical companies are coming forward with new agents that have new mechanisms of action," said Karen Bush, PhD, a distinguished research fellow at Johnson & Johnson Pharmaceutical Research & Development in Raritan, N.J.

Dr. Bush was speaking at last month's Interscience Conference on Antimicrobial Agents and Chemotherapy, in Chicago. According to informal surveys by infectious disease experts, researchers at this meeting presented data on more than 120 completely new compounds, an unprecedented number. It's too early to predict which compounds eventually will reach patients, but observers hope the heightened level of activity signals a reversal of the trend of fewer new antibiotics coming online each year.

To add momentum to the antibiotic pipeline, some experts at the meeting were advocating a change in the way scientists pursue new germ-killers. For a decade or more, research has focused on targets emerging from the genetic sequencing of various pathogens. Scientists say that although this work has been valuable with regard to increasing the understanding of these bugs, it has not fulfilled hopes for discovering new treatments. Instead, those in the field are urging scientists to return to hunting in the natural world -- the source of the earliest antibiotics.

"It's terrific that we have all these sequences now, but part of the rationale was that we would get new targets for killing [pathogens]. That has not really been productive," said Richard Baltz, PhD, a scientific fellow at Cubist Pharmaceuticals Inc. in Lexington, Mass.

Some of this work is under way. A series of papers documented the effectiveness of friulimicin B, a member of the lipopeptide class, in the test tube and animal models against gram-positive pathogens such as methicillin-resistant Staphylococcus aureus. This antibiotic is produced by the bacteria Actinoplanes friuliensis, and phase I trials are beginning.

Fighting TB: An area of promise

New developments regarding the treatment of tuberculosis also are adding to the optimism and providing important insights into strategies to fight other infections.

For instance, data were presented at the meeting regarding at least seven possibilities for tuberculosis. This condition hasn't had new treatment options for decades, and medications being investigated include completely new agents as well as old ones that are not usually used for this infection.

"We now have more tuberculosis drugs in clinical development than at any other time in history," said Melvin Spigelman, MD, director of research and development at the Global Alliance for TB Drug Development. "For doctors to have seven drugs in development is really a remarkable achievement."

In the case of TB, experts want these new approaches to address emerging resistance as well as allow patients to take fewer medications for shorter periods. TB's six-month-or-longer, multidrug regimen is viewed as one of the biggest barriers to controlling the illness.

"We have excellent tuberculosis treatment," said Dr. Jacques Grosset, a professor at the Center for Tuberculosis Research at Johns Hopkins University School of Medicine in Baltimore. "But 50% of patients don't complete the treatment that should cure them. There are a lot of failures and a lot of deaths and a lot of drug resistance because of this. We should shorten the duration of treatment because the treatment now is extraordinarily difficult to complete."

To this end, researchers presented data on a clinical trial that randomized patients to either traditional treatment or a regimen that substituted the fluoroquinolone moxifloxacin for ethambutol. After two months, 85% of patients in the experimental group had negative cultures, compared with only 68% in the control group. Another paper, also co-authored by Dr. Grosset, showed a combination of moxifloxacin, rifapentine and pyrazinamide cured this infection in a mouse model in 2.5 months.

Treatment of many infectious diseases, such as TB, requires a multitude of pills, so researchers also are looking at combining drugs at the molecular level. This concept has been tried before but has not been successful outside the test tube. Experts regard the benefits, such as the possibility of increased efficacy beyond the drugs taken individually and a reduced risk of developing resistance, so great that the pursuit continues to find a blended compound.

"The concept is worth it, and hopefully this will bear some fruit," said Harald Labischinski, PhD, CEO of Combinature Biopharm AG in Berlin. He chaired a symposium on the issue.

While some said the antibiotic development pipeline is starting to look healthier, they also expressed caution. It is not uncommon for new compounds to be announced at scientific meetings and then never be heard about again. For those agents that are investigated further, it can take a long time to move from early data to use in patients. Very few drugs actually make it the full distance.

"We will need a lot more effort to turn these compounds into drug candidates, and we will see a lot of failures along the way," said Ken Duncan, PhD, senior program officer of the Bill & Melinda Gates Foundation.




Source: AMA