Keeping an eye out for super-bugs and a nose out for new antibiotics

Researchers with the Canadian Bacterial Diseases Network (CBDN), a federal Network of Centres of Excellence, are monitoring bacterial resistance to antibiotics and crafting new antibiotics to battle mighty microbes.

Over the years, conventional antibiotics have been used so extensively that many of the bacteria that infect us daily have grown resistant to them. And with the increasing use of combinations of antibiotics, or drug cocktails, when someone has a bug that is resistant to one drug in the mix, this will often prevent the whole cocktail from working for them.

Bacterial resistance to drugs can be a problem because it often leaves a patient with no other recourse for treating their illness. And while resistance to antibiotics is a problem as old as anti-biotics themselves, it has become more of a problem today because no new classes of antibiotics have been developed in over 30 years and bacteria are learning how to outsmart existing drugs.

Dr. Diane Taylor, professor of medical microbiology and immunology at the University of Alberta, explains that in the 1980s many drug companies wishing to maximize profits shut down their antibiotic programs. But in the 1990s, she says some re-opened and a few new companies started up after they realized bacterial resistance to existing drugs was growing.

Dr. Taylor is part of a network of CBDN researchers who are busy monitoring rates of resistance to antibiotics in Canada. She has been studying Albertan rates of resistance to the antibiotic clarithromycin, used as part of the therapy to get rid of the bacteria that cause stomach ulcers. She says the antibiotic has only been widely used for about four years and resistance rates are low -- at about one per cent so far -- but she warns that we need to be forever vigilant.

In 1993 CBDN helped establish surveillance networks all across Canada targeting community and hospital settings. There had previously been no ongoing measurement of the prevalence of resistance to antibiotics.

To monitor resistance rates, CBDN researchers ask laboratory technologists in private, community and hospital labs to collect strains of certain bacteria when they identify them in patient cultures they are testing. The laboratories then send these bacteria to the central CBDN lab, where researchers test the bacteria's resistance to existing antibiotics.

Dr. Don Low is chief of the department of microbiology at Mount Sinai Hospital, University of Toronto, where the central CBDN test lab is located. He says they are trying to see the extent to which bacteria have grown resistant to antibiotics and find out how and why they've done so.

Dr. Low says there has been a phenomenal increase in the resistance of many bugs, specifically Streptococcus pneumonia -- the most common cause of bacterial sinusitis, ear infections, pneumonia and meningitis.

For example, six years ago, its resistance to penicillin was less than one per cent. Today, it has jumped to 14 per cent. The bacteria's resistance to erythromycin, a commonly used antibiotic for outpatient infections, has increased from two to six per cent. But the good news is that Dr. Low's team has discovered how and why these super-bugs have become so strong.

"What we've discovered is that these bacteria have acquired resistance genes which allow the bacteria to change the target the antibiotic (erythromycin) is aimed at so it won't be recognized," says Dr. Low. "They've acquired a gene . . . through a sort of Darwinian evolution . . . which allows them to pump the antibiotic out of the bacteria as quickly as it comes in."

Dr. Low says they look at resistance rates in given regions and these rates can help shape local policies for treatment. He explains that if you live in southern Alberta, where resistance rates to penicillin are around 13 per cent, your physician probably shouldn't prescribe it for serious infections. But if you live in Prince Edward Island, where the rates are under two per cent, your doctor probably can.

"Surveillance is the lynch-pin for preventing the problem from getting bigger," says Dr. Low. "It warns us of an impending problem we may be able to do something about now rather than later."

Researchers hope understanding resistance will allow them to develop new antibiotics. Says Dr. Low: "In order to develop new drugs, you have to understand how and why the old ones stopped working."

To this end, CBDN researchers are also developing new breeds of antibiotics that may help fend off super-bugs and battle a host of other bacteria that could not be treated before. One of these potential antibiotics, made from cationic peptides, were engineered by CBDN researchers led by Dr. Bob Hancock, professor of microbiology at the University of British Columbia.

Cationic peptides have been developed for use in topical skin creams and ointments before, but have not been developed for use against bacteria inside the body. That is, until Dr. Hancock and his team found a new way of tweaking these peptides to allow them to function by intravenous injection against serious infections in the body.

Cationic peptides have a particular electrical charge that allows them to latch onto the surface of bacterial cells with the opposite electrical charge, destroying them almost instantly. These potent peptides have a double advantage: they can act as new antibiotics and they can also enhance the effectiveness and extend the life of conventional antibiotics.

Because peptides kill so quickly, bacteria don't have much of a chance to develop resistance to them. Dr. Hancock says they haven't seen the normal resistance that usually appears in clinical trials. He says it looks promising because in research and laboratory testing so far, he and his colleagues have tried without success to get bacteria to develop resistance to the peptides.

One application for Dr. Hancock's cationic peptides is boosting resistance to infections in fish. With the help of new CBDN spin-off company Microgene International Ltd., Dr. Hancock's team is creating genetically-enhanced fish that overproduce peptides. Since 25 per cent of total aquaculture stocks are susceptible to infections, the innovation could mean more food production and a greater profit for one of Canada's growing industries.

And another recently discovered application of cationic peptides could help cystic fibrosis patients fend-off deadly Pseudomonas aeruginosa bacteria.

In 1988, Canadian researchers discovered that people with cystic fibrosis have a genetic mutation in their CFTR gene. This genetic mutation results in chronic lung infections because it causes a defect in the movement of chloride and sodium in the lungs, so saltiness accumulates. In this salty lung environment, a person's naturally occurring cationic peptides lose their ability to kill bacteria like Pseudomonas aeruginosa — a super-bug resistant to most antibiotics.

So Dr. Hancock's team went to work designing several salt-resistant peptides, in the hopes that they would allow cystic fibrosis patients to fight off infection. They are still testing peptides and trying to decide which of their creations is best. There are patents pending on the peptides.

CBDN researchers are also working on a way of putting their peptides into an aerosol spray can so patients can simply spray their lungs regularly.

Dr. Hancock says he expects to have the technology into clinical trials within the next one to three years. If the results there are promising, industrial partner Micrologix Biotech Inc. says it will seek to license the technology from CBDN and move it forward into drug development.

Dr. Hancock and his team of researchers received funding to explore these new peptides both from a $500,000-a-year grant awarded to them by the Canadian Cystic Fibrosis Foundation and through federal government funding for CBDN.

CBDN, which links 58 investigators at 15 Canadian universities and four government laboratories with 88 industrial partners and affiliates, is one of 14 Networks of Centres of Excellence (NCE). The NCE program receives $47.4 million a year from Industry Canada, the Natural Sciences and Engineering Research Council, the Medical Research Council, and the Social Sciences and Humanities Research Council. The NCE funds going to CBDN represent an average annual investment of over $3.8 million in Canadian research and development.

For more information please visit the CBDN Web Site.