Understanding Resistance

Researchers Uncover How Microbes Evade The Immune System

By David Lawrence

The human body is host to some 10 trillion microbes. While bacteria are beneficial in regions of the body such as the digestive track, other areas including the blood and lungs need to remain sterile. So how does the body maintain a healthy flora of microbes where they should be, while keeping them out of areas where they shouldn't?

The answer involves a class of immune molecules known as antimicrobial peptides (AMPs). These molecules are one type of the body's natural antibiotics, which are launched against bacteria when they try to infect sensitive areas.

Immune peptides are so effective at eliminating bacteria that pharmaceutical companies have begun developing AMP-based antibiotics. These drugs have been touted as a promising alternative to conventional antibiotics because issues of bacterial resistance were considered improbable. However, researchers have uncovered new evidence that challenges this concept.

A microbiology team based at the University of Washington (UW) recently found that Salmonella typhimurium, a disease-causing microbe that commonly contaminates food, exhibits natural resistance to immune peptides. This microbe can sense the onslaught of AMPs with a special surveillance system, a receptor that projects from its membrane. Once the receptor has been activated, it signals the cell to prepare for attack, allowing the bacteria to resist AMPs and survive.

This research, led by UW microbiologists Samuel Miller and Martin Bader and their colleagues at McGill University in Montreal, was published in the August edition of the journal Cell.

Based on these findings, novel drugs could be developed to target this bacterial receptor. But instead of using AMPs as antibiotics to fight infection, which could encourage microbial resistance, a safer strategy may be to devise a way to hinder the microbes' AMP receptor, making otherwise resistant microbes vulnerable to the immune system.

Resistance Is . . . Not So Futile

Some experts have suggested that resistance to AMPs would be rare because their target, the membrane, is a feature so fundamental to the organism that it would be difficult to mutate.

However, according to Graham Bell, a biologist from McGill University, evolution of AMP resistance in microbes is not only possible, but likely.

Bell and several colleagues recently conducted a study in which two species of bacteria were exposed to steadily increasing doses of Pexiganan, an AMP-based drug that underwent FDA clinical trials. Both microbes evolved resistance to this antibiotic after 600 to 700 generations.

This work has profound implications for the development of AMP pharmaceuticals.

Bell's team speculates that if human AMPs are administered as antibiotics, bacteria will develop resistance to them, therefore short circuiting the body's natural defense system.

The result may be "frequent failure of minor cuts and scrapes to heal properly" and "greater severity of diseases caused by chronic infection," according to Bell and coauthor Pierre-Henri Gouyon in a 2003 Microbiology article. They conclude, "Instead of dismissing the possibility that widespread resistance will evolve, we should use the bitter experience that we have gained from conventional antibiotics to plan for it.”

Natural resistance to AMPs may be quite widespread. "Almost all of the gram negative bacteria have the genes involved in this [resistance]," says Miller. "Antibiotic resistance is a huge problem. There will be some development of resistance to anything that kills bacteria.”

Research conducted in Fiona Brinkman's laboratory at Simon Frasier University suggests microbes have a larger 'arsenal' of genes involved in resistance than previously thought. Based on her work describing the genome of bacteria, or the total genetic contents of the cell, scientists have begun to appreciate the capacity of bacteria to resist antibiotics.

Drugs that target and hinder natural resistance mechanisms of bacteria, such as the receptor described by Miller's team, may provide a hopeful antibiotic substitute. Instead of administering AMPs to kill infecting microbes, this tactic would silence the bacteria's surveillance system and allow the body's own AMPs to do their job. While this strategy is promising, Miller says the development of such drugs is far in the future.

David Lawrence is a research biologist at the University of Washington.

Image at Top:

Color-enhanced scanning electron micrograph showing Salmonella typhimurium (red) invading human cells. Image: Rocky Mountain Laboratories, NIAID, NIH