Saturday, 11 May 2019

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.

The idea of the new study 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.

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.

Many antibiotics 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.

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.

READ MORE: Fungus provides powerful medicine in fighting honey bee viruses

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.

The researchers 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.

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.

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.

Research paper:

The antimicrobial potential of Streptomyces from insect microbiomes. Nature Communications, 2019; 10 (1) DOI: 10.1038/s41467-019-08438-0

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology

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