Compound that kills drug-resistant fungi is isolated from ant microbiota
Antimicrobial and antifungal
resistance, which describe the ability of bacteria and other pathogens to
resist the effects of drugs to which they were once sensitive, is a major
public health problem worldwide. A study published recently in the journal Nature
Communications suggests that the solution may come from the tiny bodies of
insects, or more accurately, from the microbiota that they host.
This innovative
hypothesis was first proposed by Brazilian and US researchers as part of a
collaborative project begun in 2014 with support from FAPESP and the US
National Institutes of Health (NIH).
The idea was to
isolate bacteria that live in symbiosis with leafcutting ants of the genus Atta
and to look for natural compounds with the potential to yield new drugs (read
more at: agencia.fapesp.br/19498).
By pursuing this
strategy, a research group led by Monica Tallarico Pupo, Professor of Medicinal
Chemistry at the University of São Paulo’s Ribeirão Preto School of
Pharmaceutical Sciences (FCFRP-USP), and Jon Clardy, Professor of Biological
Chemistry and Molecular Pharmacology at Harvard Medical School in the US,
discovered cyphomycin, which, when tested in vitro and in vivo, was shown to be
capable of killing fungi that cause diseases in humans and are resistant to currently
available drugs.
"It was an
exciting discovery because it confirmed our hypothesis that the insect
microbiota is a promising source for the isolation of compounds with
antibacterial and antifungal activity. Of course, it's too soon to know whether
cyphomycin will become a drug, but we’ve made sufficient progress to apply for
a patent," Pupo told Agência FAPESP.
Many antibiotics, she
added, originate from compounds produced by bacteria found in soil. Most of
these bacteria belong to the genus Streptomyces. The researchers decided to
investigate this same group of filamentous bacteria in insect bodies. Their
hypothesis was that if the bacteria help insects defend against pathogens, they
might play the same role in humans.
"Soil was
thoroughly explored at the time the first antibiotics were discovered and
produced," Pupo said. "We wanted to find a new ecological niche. We
set out to confirm whether evolutionary pressure made the bacteria hosted by
insects even more effective against pathogens."
Specimens were
collected by collaborators from the US, Costa Rica and Panama. In addition to
leafcutting ants of the tribe Attini, butterflies, wasps, bees and moths were
included, for a total of 1,400 insects.
"In Brazil, more
than 300 ant colonies were collected in the Cerrado [Brazilian savanna],
Atlantic Rainforest and Amazon biomes. Cyphomycin was isolated in one specimen
of the genus Cyphomyrmex collected on the University of São Paulo’s Ribeirão
Preto campus," Pupo said.
After the insects were
collected, the bacteria found in their bodies were isolated, purified in the
laboratory, and tested in vitro against microorganisms that act as pathogens in
humans. The species that proved most effective against these pathogens were
selected for metabolomic analysis - to characterize the metabolites they
produce and identify the most active of these - and for phylogenetic studies,
in which gene sequencing indicated to what extent the insect-associated
bacteria resembled the strains of Streptomyces that live in soil.
"We combined
chemometrics and liquid chromatography coupled with mass spectrometry to
profile the compounds produced by the insect microbiota. The aim was to
identify the Streptomyces strains that produce a distinctive chemistry - in
other words, to find compounds quite different from those synthesized by soil
bacteria. In this way, we increased the likelihood of finding a genuinely
innovative molecule," Pupo explained.
The compounds shown to
be most effective by these rigorous methods were tested again, in vitro and in
mice, against pathogens resistant to the drugs used in clinical practice.
According to Pupo,
cyphomycin was not effective against bacteria but proved capable of combating
infection by Aspergillus fumigatus, the fungus most frequently found in hospital-acquired
infections and the cause of aspergillosis, a disease with an attributable
mortality as high as 85% even after antifungal treatment.
When administered to
laboratory animals, cyphomycin also combated infection by Candida glabrata and
C. auris, fungi that cause candidiasis in humans and are resistant to existing
drugs.
"Cyphomycin
wasn’t the first compound with antimicrobial action identified in our project,
but no others displayed this level of activity," Pupo said.
The part of the study
that developed the chemical profile of the bacterial compounds was performed
during the PhD research of Humberto Enrique Ortega Dominguez with FAPESP's
support and supervision by Pupo at FCFRP-USP. During a postdoctoral research
internship at the University of Wisconsin-Madison in the US, with supervision
by Tim Bugni and a scholarship from FAPESP, Dominguez focused on metabolomic
studies and isolated cyphomycin, finalizing its structural determination after
his return to Brazil. The trials with mice were conducted by David Andes and
his group at UW-Madison.
Weilan Gomes da Paixão
Melo, a postdoctoral researcher with a scholarship from FAPESP, participated in
insect collection and in microbiota isolation and identification. She also
performed phylogenetic studies during a research internship in Cameron Currie's
laboratory at UW-Madison.
Marc G Chevrette,
Caitlin M Carlson, Humberto E Ortega, Chris Thomas, Gene E Ananiev, Kenneth J
Barns, Adam J Book, Julian Cagnazzo, Camila Carlos, Will Flanigan, Kirk J
Grubbs, Heidi A Horn, F Michael Hoffmann, Jonathan L Klassen, Jennifer J Knack,
Gina R Lewin, Bradon R McDonald, Laura Muller, Weilan GP Melo, Adrián A
Pinto-Tomás, Amber Schmitz, Evelyn Wendt-Pienkowski, Scott Wildman, Miao Zhao,
Fan Zhang, Tim S Bugni, David R Andes, Monica T Pupo, Cameron R Currie.
The antimicrobial potential of Streptomyces from insect microbiomes.
Nature Communicationsvolume 10, Article number: 516 (2019). doi: 10.1038/s41467-019-08438-0.
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