Synthetic antibiotics that punch holes in cell membranes can cure mice with an otherwise lethal bacterial infection, researchers report in the 26 July issue of Nature. Biochemists hope that the results will lead to a flexible new class of drugs effective against antibiotic-resistant bacteria.
In the 1980s, scientists discovered that animals produce peptides that serve as natural antibiotics; they break holes in cell membranes, causing bacteria to leak to death. Peptides seemed enormously promising as drugs because bacteria cannot easily alter their membranes to become resistant, as they have against many older antibiotics. Several peptide-based drugs are in clinical trials, but their success has been limited. One problem is because of their large size, they're less mobile than older antibiotics, which makes it difficult to deliver them to the site of infection.
Biochemist M. Reza Ghadiri and his colleagues at the Scripps Research Institute in La Jolla, California, have developed a class of synthetic peptides that circumvent this problem. Their new molecules are thin rings of just six to eight amino acids, which travel easily; only after they reach the bacterial cell membrane do they spontaneously form hydrogen bonds and build stacks that function like other peptides. The insertion of several stacks strains the membrane to the breaking point.
Researchers can easily change the amino acid building blocks of the rings and then screen whether the resulting peptide is effective against different microbes. When Ghadari and his co-workers injected peptides selected for potency against the pathogen Staphylococcus aureus into mice suffering from a bad infection with that bug, 100% of them survived for the entire 1-week trial. The controls all died within 2 days.
With their on-the-spot assembly, the team has remedied a major weakness of natural peptides, says Tomas Ganz, a biochemist at the University of California, Los Angeles. And that's important, Ganz says, because drug designers are "running out of ... new structures for antibiotics."