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Learning to fight an adversary that won't stay down

New biomolecular technologies have largely failed to deliver the hoped-for knockout punch breakthrough against the defences of disease-causing bacteria, says a leading Canadian specialist in antibiotic resistance.

Techniques such as genomic sequencing and high throughput screening were expected to make the development of new antibiotic compounds easier and more productive. But in most cases the microbes continue to hold the upper hand ?and if three billion years of bacterial history is any kind of track record, we're in for an endless running battle, says Dr. Julian Davies, a microbiologist at the University of British Columbia.

"We haven't evolved in our thinking sufficiently to be able to match the microbes," says Dr. Davies, Scientific Director of the Canadian Bacterial Diseases Network. "Pharmaceutical companies and other researchers have put hundreds of millions of dollars into 'modern' approaches to antibiotic discovery over the past six or seven years and this has failed miserably."

The scientist, whose work is supported by Science and Engineering Research Canada (NSERC), has organized a symposium on the evolutionary genetics of antibiotic resistance at the 2005 meeting of the American Association for the Advancement of Science in Washington D.C.

The ongoing appearance of new pathogen varieties like multi-resistant E. coli and Staphylococcus aureus (MRSA), the bacterium that causes methicillin-resistant tuberculosis, provide good examples of the challenges we face, says Dr. Davies.

Ironically, he says, advances in molecular biology techniques have shown just how adept these pathogens are at adapting to anything we can throw at them. Innovations such as highly efficient polymerase chain reaction (PCR) have made it possible to identify and study the many genes responsible for antibiotic resistance in hospitals and the environment.

"What has been found is that there are more antibiotic resistance genes around than w e ever realized," says Dr. Davies. "There are more than 300 genes now known that confer resistance to one or more antimicrobials. And they keep coming."

However, the mapping of bacterial genomes has not yet helped yield solutions to the problem, says Dr. Davies.

He adds that our understanding of the activity of microbes must extend beyond the newspaper headlines reporting outbreaks of these "superbugs," so that we can put the role of these organisms in the proper evolutionary perspective. This subject, and antibiotic resistance in particular, has fascinated Davies since he began postdoctoral work on antibiotics and resistance mechanisms at Harvard Medical School in the early 1960s.

"The microbes are evolving genetically, and the pharmaceutical companies are evolving chemically; the two don't match," says Dr. Davies, adding that doctors who deal with microbial diseases in hospitals must remain cautious about exposing the bacterial pathogens to the newest and most effective drugs so as to avoid overuse and the accompanying onset of resistance.

"There are a relatively small number of antibiotics that have come out that are new, and some of them are very potent and act against most resistant strains," he says. "But the clinicians rightly try to keep these things in reserve for when they are really needed."


Source:Natural Sciences and Engineering Research Council

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