When a bacterium evolves resistance to a particular antibiotic, it's problematic. When it evolves defenses against antibiotics in general, as Pseudomonas aeruginosa has done, it's terrifying. But now researchers have devised an antibiotic that attacks the germ in a completely new way that appears to overwhelm those defenses.
P. aeruginosa is a highly adaptable bacterium that lives almost everywhere. Although a healthy immune system can stop it from causing serious problems, it mercilessly exploits almost any weakness in immuno-compromised people. It is the fourth most common cause of hospital-acquired infections, attacking burn victims and triggering septicemia and pneumonia in leukemia and AIDS patients. Pseudomonas-induced lung infections contribute to the deaths of almost all cystic fibrosis patients.
The bacterium is resistant to antibiotics because of its nearly impermeable cell wall, which makes it very difficult for the drugs to enter the microbe. And if they do sneak past security, the antibiotics may have a very short stay: the bacterium has evolved "efflux pumps" that eject unwanted chemicals. Many infected with P. aeruginosa have to be treated with antibiotics previously considered too toxic for human use.
To find an alternative, chemist John Robinson and colleagues at the University of Zurich in Switzerland teamed up with scientists at pharmaceutical company Polyphor, also in Switzerland, to mimic the body's own defenses against the devilish bug. The healthy immune system produces molecules called peptides that attack the bacterium's formidable cell wall, and scientists have long speculated about the potential of synthetic peptides as antibiotics. But peptides themselves have serious problems-the human body breaks them down very quickly, and they can be toxic in high doses. "Although the starting point for our work is often peptides and proteins from the natural world, we want to make something which is more stable, more effective, and less toxic," says Robinson.
In this week's Science, the researchers describe a synthetic molecule called a peptidomimetic that disrupts the function of LptD, a bacterial protein never before targeted by an antibiotic. The group based the new compound on a natural antimicrobial peptide called protegrin-I but tweaked its molecular structure enough that the peptide binds to LptD instead of the lipid molecules protegrin-I targets. Because LptD is found only in Pseudomonas, the drug doesn't attack other organisms or the infected host's cells and is far less toxic than protegrin-I itself. The LptD protein protrudes from the outside of the cell wall, so the peptidomimetic can do its deadly work from outside the bacterium, neatly sidestepping the bacterium's internal antibiotic efflux pumps. In addition, the peptidomimetic lasts longer in the bloodstream than peptides themselves, because enzymes don't recognise the synthetic molecule and break it down.
Robinson and colleagues tested the potential drug on mice with Pseudomonas-induced septicemia and achieved a 100% cure rate with no apparent side effects. As a bonus, tissue culture testing indicates that the drug's ability to disable the LptD protein makes the cell wall more permeable, allowing other antibiotics used in combination with the peptidomimetic to gain access to the inner cell and work more effectively.
Robert Hancock, a microbiologist at the University of British Columbia in Canada who was involved in the discovery of the Pseudomonas cell wall's impermeability in 1982, is impressed by the study. "When I first looked at it I had some doubts because [the protein]'s such a novel target, but I really found it very exciting." Still, he sounds a note of caution. "They really haven't adequately tested the issue of toxicity yet."
Robinson responds that, since submitting the paper, Polyphor has completed a full preclinical toxicology study and is now preparing an application to begin the first human trial. "If it's approved, it'll probably take place in the summer," he says.