Bio-antibiotics?

Mark Merchant takes blood sample from an alligator.

Troy Merchant

Alligator wounds are a remarkable thing. Within only 12-24 hours, gators' torn tissue begins a healing process that takes five days to start in humans. And even though gators swim in microbe-infested waters, their wounds almost never become infected. This healing ability caught the eye of Mark Merchant, a researcher at Lake Charles, Louisiana-based McNeese State University. "I just grew up fishing in gator country and was curious to learn about their immune system," he says. "I didn't set out to discover a new antibiotic."

In fact, Merchant found that gator leukocytes secrete small peptides capable of killing many of the microbes that modern antibiotics can't touch, including MRSA - a resistant strain of Staphylococcus aureus thought to be responsible for 70% of the lethal infections contracted in US hospitals. He is part of a group of researchers turning to nature in search of proteins and peptides that kill deadly microbes, now that traditional sources are drying up.

Ever since a soil mold, Penicillium notatum, floated through an open window in Alexander Fleming's lab in 1928, and killed bacterial specimens growing in an open Petri dish, scientists in search of new antibiotics have looked to fungi. But attempts to revamp existing drugs have met only limited success. Despite high-throughput methods that test synthetic compounds, and meta-genomic screens that identify antibiotic-producing clusters of DNA, only a few new candidates have been identified.

Like Fleming's chance discovery, many new antibiotics are the product of fate.

While looking for an industrial enzyme to make iron-free shirts and strengthen paper, the Denmark-based biotechnology company, Novozymes, found a rare antibiotic peptide in Pseudoplectania nigrella, a black fungus that grows in European pine forests. "We analyzed the sequences of every peptide and protein secreted by the fungal cells," says Hans-Henrik Kristensen, a senior manager at Novozymes. "We realized that one of them [was similar] to a known class of antibiotic peptides called defensins."

Named plectasin, Novoymes' defensin kills aggressive strains of Streptococcus pneumoniae. Since the 2005 discovery, the company has screened more than 660 variants of the peptide, and identified the most potent one. Animal trials are underway, and the company hopes to move the peptide to the clinic in 2010. "It's a lovely example of the serendipity often associated with large discoveries," says Kristensen (Nature, 437:975-80, 2005).

Yet protein and peptide-based antibiotics are not without their pitfalls-unlike other biologic drugs, they have to be delivered in high doses. "Antibiotics have to be administered in large quantities, up to several grams a day," says Kristensen. "This requires a high safety and tolerance margin."

Mass-producing proteins and peptides is also more costly than making a small-molecule-based antibiotic, in part because protein expression is as much an art as a science, says Kristensen. The problem is that the lab techniques used to mass-produce antibiotics rely heavily on fungal cells, and have been developed over the years to cater specifically to the antibiotics found in molds; you usually can't express genes from other animals in fungal systems without a lot of problems, says Kristensen.

So far, plectasin is the only biologic antibiotic (and the only defensin) found in fungi, which enables this unique type of antibiotic to be mass-produced. Although other defensins have been found in humans, fireflies, and other animals, scientists have not been able to make high-enough quantities to conduct animal tests.

Merchant has faced similar difficulties. "The fact that the proteins come from gators has caused all kinds of problems," he says. "They are very hard to isolate." While national headlines have touted Merchant's antibiotics as the new cure for superbugs, he has so far been unable to study their structure or sequence. It will thus be years before dosage trials can even begin on animals, let alone humans.

Yet Merchant remains optimistic. "We don't really have much of a choice," he says. "We have to find antibiotics that employ new mechanisms, even though the research can be frustrating at times."