Farming Ants’ Bacterially-Produced Antibiotic Weapon Identified

One of the selective antibiotics attine ants use to protect their fungal gardens has just been isolated and structurally described by Jon Clardy and colleagues from the Harvard Medical School in Boston and the University of Wisconsin in Madison. Although the mutualism between attine ants and actinobacteria is arguably the best studied of all ant-bacterial relationships, this is the first characterization of a chemical that strongly suppresses the growth of a garden predator but not the cultivated fungus. Its discovery is expected to help scientists gain greater insights into the molecular evolution of these complex symbiotic communities, some of which are at least 50 million years old, as well as lead to the development of more effective anti-fungal agents.

The newly characterized antibiotic, called “dentigerumycin” in honor of Apterostigma dentigerum, the fungal-farming ant species which choreographed its evolution, was reported online in the 29 March 2009 Nature Chemical Biology. (Doi:10.1038/nchembio.159) The researchers describe dentigerumycin as “an actinobacterially-produced cyclic depsipeptide containing unusual amino acids —piperazic acid, γ-hydroxypiperazic acid, β-hydroxyleucine and N-hydroxyalanine —with the molecular formula C₄₀H₆₇N₉0₁₃.” Petri dish assays show that it actively inhibits Escovopis while largely sparing the ant’s fungal cultivar. Notably, dentigerumycin was also able to slow the growth of a drug-resistant strain of Candida albicans, a human pathogen that is becoming increasingly impervious to existing anti-fungal drugs.

But dentigerumycin is not the only game in attine-ant town: “Pseudonocardia evolved a variety of small molecules over their long evolutionary history with fungal-farming ants with different bacterial strains producing different antibiotics,” says Clardy. “In fact,” adds Currie, a member of the dentigerumycin discovery team, “attine ants are walking pharmaceutical factories. Each ant colony,” he notes, “maintains a specific bacterial strain and can differentiate between it and foreign actinomycetes.” Finding out how individual ant species and their distinct bacterial sidekicks cope with the specialized parasites that prey on their different fungal crops is expected to yield an array of novel antibiotics.

As an added bonus, ant colonies also seem to be “miniature biofuel reactors,” Currie says. A single colony feeds their garden fungi up to 400 kilograms of leaves (dry weight) a year and, somehow, the cellulose gets digested. Metagenomic studies of leaf-cutting ant colonies detected the genetic signatures of cellulose-digesting fungus as well as many bacterial species also capable of breaking down tough plant material. Transferring these skills to the laboratory has so far proved difficult; however, Currie speculates that “the newly discovered bacterial and fungal enzymes may be efficient at digesting cellulose because they’ve evolved for thousands of years along with the ants and a better understanding these long-term relationships may help us in our own attempts to break down plant biomass.”

“It’s findings such as these that should fire the imagination of aspiring microbiologists,” says Thomas Eisner, Professor Emeritus of Chemical Ecology at Cornell University in Ithaca, New York. “Think of the myriad of microbial interactions awaiting discovery and the body of knowledge that will be derived from characterization of their mediating chemicals,” adding “If I had to do it all over again, I’d go into microbial ecology.”

Rodney L. Levine from NIH’s National Heart, Lung, and Blood Institute agrees with Curtis adding that “perhaps it’s sunlight, perhaps it’s desiccation, organisms which evolve or induce a resistance to one stress are often resistant to multiple other stresses.” But, he says, “as Daly has pointed out, we live in a DNA-centric world which holds that cells die because of genome injury and this is not entirely correct. Deinococcus’ DNA is as diced and sliced by irradiation as that of E. coli, but Deinococcus survives when Escherichia dies. Daly’s experimental data show why this happens; it’s all about the proteins.”