Nature’s path leads to new antibiotic strategy

By mimicking one of nature’s own potent antimicrobial defenses, scientists may have found a new way to wage war on pathogenic bacteria.

Writing in the British scientific journal Nature (April 6), a team of university scientists report the design, synthesis and evaluation of a new type of molecule that exhibits a wide spectrum of antimicrobial activity, including against two species of bacteria that are resistant to common antibiotic drugs.

The work is important because it demonstrates the feasibility of developing a new class of antibiotics that can potentially overcome the growing resistance of disease-causing bacteria to current medicines, according to UW–Madison chemistry Professor Samuel H. Gellman, an author of the new study. Moreover, the work reveals the potential of using nature as a guide to build medically important synthetic molecules that can outperform their naturally occurring counterparts.

“Nearly all antimicrobial agents now used in clinical settings are naturally occurring molecules, or are closely related to molecules found in nature,” Gellman says. “In contrast, our new antimicrobials are very different from all molecules found in nature. The upshot of this research is that we may be on a radical new path that may lead to the rational, deliberate design of clinically useful molecules like antibiotics.”

The design of the new antibacterial agents involved mimicry of naturally occurring peptides that ward off microbial invasion.

Peptides are composed of alpha-amino acids, which also are the building blocks of protein molecules and are essential to all life. In nature, peptides can be selectively toxic to invading microorganisms, forming a first line of antimicrobial defense in everything from plants to people. The natural antibiotic peptides, however, are rapidly degraded in living tissues and can be highly toxic to human cells in addition to infectious bacteria.

The Wisconsin team used unnatural, synthetic building blocks to construct the new antibiotic agents. It is possible, says Gellman, that these synthetic molecules, known as beta-peptides, will be “intrinsically better than the kinds of peptides found in nature” because they are both more stable and, in therapeutic doses, less toxic to human cells.

“We think our molecules mimic the antimicrobial mechanism of naturally-occurring peptides,” Gellman explains. “Before, it has never been possible to mimic this antibiotic mechanism with such fundamentally unnatural molecules.”

There is plenty of reason to think that the technology can go far, Gellman says in an interview. “In terms of antibacterial activity, we’ve already matched the benchmark. Because our molecules are unnatural they shouldn’t be readily degraded, and they have well-defined, predictable shapes” that can be customized to confront specific pathogenic bacteria.

Already, the new molecule built in Gellman’s lab has proved to be effective in the laboratory against an array of infectious bacteria, including strains of two species (Enterococcus faecium and Staphylococcus aureus) dreaded by physicians because of their resistance to conventional antibiotics.

Although scientists do not yet know precisely how natural antimicrobial peptides kill bacteria, they believe that these natural peptides pierce the microbe’s outer surface and gum up its inner workings.

“These things seem to be able to disrupt the bacterial membrane. When that happens, all hell breaks loose with the bacterium,” Gellman says.

This mechanism of thwarting bacterial infection is different from that employed by traditional antibiotics like penicillins, for example, suggesting that it might take a very long time for bacteria to evolve defenses against it.

“We don’t think our new molecules will be compromised very quickly by resistance. These beta-peptides have no precedents in nature, unlike traditional antibiotics. Chemically, they are completely unlike the kinds of things bacteria typically see,” says Gellman.

“The nice things about these new molecules is that they have a very low toxicity” when exposed to human cells, according to Bernard Weisblum, a UW–Madison professor of pharmacology and a co-author of the Nature paper. “They seem to coexist pretty well with red blood cells.”

What’s needed now to advance the technology, Weisblum says, is a better understanding of how these synthetic beta-peptides affect the biology of living organisms.

In addition to Gellman and Weisblum, other authors of the Nature paper include Emilie A. Porter, Xifang Wang and Hee-Seung Lee, all of UW–Madison. The research was funded initially by the National Science Foundation, and more recently by the National Institutes of Health.

Gellman’s group has applied for a patent on the synthetic peptides through the Wisconsin Alumni Research Foundation or WARF, a private not-for-profit organization that manages intellectual property on behalf of UW–Madison faculty and staff.