Scientists ponder the peat bog to fight TB

The environment of a peat bog is in a certain way similar to that of a human lung infected with Mycobacterium tuberculosis (TB). Both environments are acidic and low in oxygen, nutrients, and resources. As such, close bacterial relatives of M. tuberculosis inhabit these peat bogs, but they are not the only denizens of that ecosystem. Many types of fungi compete with mycobacteria for limited resources, and some of these fungi have ways to kill mycobacteria. Because M. tuberculosis is so closely related to the mycobacteria found in the bog, fungi that kill these relatives may be able to kill TB, too.

A new paper in PLOS Biology (DOI: 10.1371/journal.pbio.3002852) sampled 1,500 fungi species found in a peat bog in the Sunkhaze Meadows National Wildlife Refuge in Maine.

All of them were exposed to M. tuberculosis, and the researchers isolated five that secreted a substance that killed the bacteria. Three of the five species secreted patulin, one secreted citrinin, and one secreted nidulalin A; all three of these substances target and inactivate the thiols in M. tuberculosis that are necessary for homeostasis.

“TB is pretty easy to kill in a test tube, but it’s pretty hard to kill in the human lungs,” says Clifton E. Barry III, chief of the tuberculosis research section at the National Institute of Allergy & Infectious Diseases (NIAID) and the study’s lead researcher. While researchers have found vulnerabilities in the bacteria, all of that work has been done in the lab, not in an environment like a human lung. But since this bog environment is so similar to the TB-infected lung, “the peat bog is giving us this huge clue that really the most vulnerable metabolic process in M. tuberculosis, under conditions like they grow in humans, is thiol homeostasis,” Barry says.

Crucially, the three compounds found—patulin, citrinin, and nidulalin A—are not good drug candidates on their own. Patulin and citrinin are known mycotoxins that are poisonous to humans. But their mechanism of deactivating M. tuberculosis gives researchers another starting point to find new antituberculars. Barry sees more potential in targeting not the thiols but the enzymes that process the thiols. He says that this is because thiols are also present in eukaryotic cells, but bacteria are likely to have different thiol-processing enzymes than eukaryotic cells, which would be less toxic for humans.

William Bishai, the codirector of the Johns Hopkins Center for Tuberculosis Research and who was not involved with the research, says that the thiol disruption is interesting but that the methods used—specifically, coculturing the fungi with M. tuberculosis—are the bigger takeaway.

“I think that the real advance here is that it reminds us that microbes have coevolved. And therefore, if we want to look for natural products that kill M. tuberculosis, it probably is important to stimulate the other microbe that one is interrogating with M. tuberculosis,” he says.