Tag Archives: antifungal agent

Keanu Reeves molecule: protector of plants?

Courtesy: Wallpaperstopick [downloaded from https://wallpaperstopick.blogspot.com/2012/05/keanu-reeves.html]

The Keanu Reeves molecule is produced by bacteria.according to a February 6, 2023 news item on phys.org,

Bacteria of the genus Pseudomonas produce a strong antimicrobial natural product, as researchers at the Leibniz Institute for Natural Product Research and Infection Biology (Leibniz-HKI) have discovered. They proved that the substance is effective against both plant fungal diseases and human-pathogenic fungi. The study was published in the Journal of the American Chemical Society and highlighted in an editorial in Nature.

A February 6, 2023 Leibniz Institute for Natural Product Research and Infection Biology – Hans Knoell Institute (Leibniz-HKI) press release (also on EurekAlert) by Charlotte Fuchs, which originated the news item, highlights both the published study and the special article in Nature magazine, Note: A link has been removed,

The newly discovered natural product group of keanumycins in bacteria works effectively against the plant pest Botrytis cinerea, which triggers grey mould rot and causes immense harvest losses every year. But the active ingredient also inhibits fungi that are dangerous to humans, such as Candida albicans. According to previous studies, it is harmless to plant and human cells.

Keanumycins could therefore be an environmentally friendly alternative to chemical pesticides, but they could also offer an alternative in the fight against resistant fungi. “We have a crisis in anti-infectives,” explains Sebastian Götze, first author of the study and postdoc at Leibniz-HKI. “Many human-pathogenic fungi are now resistant to antimycotics – partly because they are used in large quantities in agricultural fields.”

Deadly like Keanu Reeves

The fact that the researchers have now found a new active ingredient in bacteria of the genus Pseudomonas is no coincidence. “We have been working with pseudomonads for some time and know that many of these bacterial species are very toxic to amoebae, which feed on bacteria,” says study leader Pierre Stallforth. He is the head of the department of Paleobiotechnology at Leibniz-HKI and professor of Bioorganic Chemistry and Paleobiotechnology at Friedrich Schiller University in Jena. It appears that several toxins are responsible for the deadly effect of the bacteria, of which only one was known so far. In the genome of the bacteria, the researchers have now found biosynthesis genes for the newly discovered natural products, the keanumycins A, B and C. This group of natural products belongs to the nonribosomal lipopeptides with soap-like properties.

Together with colleagues at the Bio Pilot Plant of the Leibniz-HKI, the researchers succeeded in isolating one of the keanumycins and conducting further tests. “The lipopeptides kill so efficiently that we named them after Keanu Reeves because he, too, is extremely deadly in his roles,” Götze explains with a wink.

The researchers suspected that keanumycins could also kill fungi, as these resemble amoebas in certain characteristics. This assumption was confirmed together with the Research Centre for Horticultural Crops at the University of Applied Sciences Erfurt. There, Keanumycin was shown to be effective against grey mould rot on hydrangea leaves. In this case, culture fluid that no longer contained bacterial cells was sufficient to significantly inhibit the growth of the fungus.

“Theoretically, the keanumycin-containing supernatant from Pseudomonas cultures could be used directly for plants,” says Götze. Further testing will be carried out together with the colleagues in Erfurt. Keanumycin is biodegradable, so no permanent residues should form in the soil. This means that the natural product has the potential to become an environmentally friendly alternative to chemical pesticides.

Fungal diseases such as Botrytis cinerea, which causes grey mould rot, cause immense harvest losses in fruit and vegetable cultivation every year. More than 200 different types of fruit and vegetables are affected, especially strawberries and unripe grapes.

Possible applications in humans

“In addition, we tested the isolated substance against various fungi that infect humans. We found that it strongly inhibits the pathogenic fungus Candida albicans, among others,” says Götze.

Instead of plants, Keanumycin could therefore possibly also be used in humans. According to the tests conducted so far, the natural product is not highly toxic for human cells and is already effective against fungi in very low concentrations. This makes it a good candidate for the pharmaceutical development of new antimycotics. These are also urgently needed, as there are very few drugs against fungal infections on the market.

The work was supported by the Werner Siemens Foundation, the Leibniz Association and the German Research Foundation (Deutsche Forschungsgemeinschaft, DFG) as part of the Balance of the Microverse Cluster of Excellence, and funded by the Dr. Illing Foundation.

The study was highlighted by Nature in a “News & Views” article.

Here are citations and links to both the published study and the article in Nature,

Ecological Niche-Inspired Genome Mining Leads to the Discovery of Crop-Protecting Nonribosomal Lipopeptides Featuring a Transient Amino Acid Building Block by Sebastian Götze, Raghav Vij, Katja Burow, Nicola Thome, Lennart Urbat, Nicolas Schlosser, Sebastian Pflanze, Rita Müller, Veit G. Hänsch, Kevin Schlabach, Leila Fazlikhani, Grit Walther, Hans-Martin Dahse, Lars Regestein, Sascha Brunke, Bernhard Hube, Christian Hertweck, Philipp Franken, and Pierre Stallforth. J. Am. Chem. Soc. 2023, 145, 4, 2342–2353 DOI: https://doi.org/10.1021/jacs.2c11107 Publication Date:January 20, 2023 Copyright © 2023 The Authors. Published by American Chemical Society

and

Bacterial defence repurposed to fight blight (News and Views article) by Andrew Mitchinson. Nature 614, 39 (2023) DOI: https://doi.org/10.1038/d41586-023-00195-x Published: 30 January 2023

Both the study and the ‘News and Views’ article are behind a paywall.

Is there a risk of resistance to nanosilver?

Anyone who’s noticed how popular silver has become as an antibacterial, antifungal, or antiviral agent may have wondered if resistance might occur as its use becomes more common. I have two bits on the topic, one from Australia and the other from Canada.

Australia

Researchers in Australia don’t have a definitive statement on the issue but are suggesting more caution (from a March 31, 2017 news item on Nanowerk),

Researchers at the University of Technology Sydney [UTS] warn that the broad-spectrum antimicrobial effectiveness of silver is being put at risk by the widespread and inappropriate expansion of nanosilver use in medical and consumer goods.

As well as their use in medical items such as wound dressings and catheters, silver nanoparticles are becoming ubiquitous in everyday items, including toothbrushes and toothpaste, baby bottles and teats, bedding, clothing and household appliances, because of their antibacterial potency and the incorrect assumption that ordinary items should be kept “clean” of microbes.

Nanobiologist Dr Cindy Gunawan, from the ithree institute at UTS and lead researcher on the investigation, said alarm bells should be ringing at the commercialisation of nanosilver use because of a “real threat” that resistance to nanosilver will develop and spread through microorganisms in the human body and the environment.

A March 31 (?), 2017 University of Technology Sydney press release by Fiona McGill, which originated the news item, expands on the theme,

Dr Gunawan and ithree institute director Professor Liz Harry, in collaboration with researchers at UNSW [University of New South Wales] and abroad, investigated more than 140 commercially available medical devices, including wound dressings and tracheal and urinary catheters, and dietary supplements, which are promoted as immunity boosters and consumed by throat or nasal spray.

Their perspective article in the journal ACS Nano concluded that the use of nanosilver in these items could lead to prolonged exposure to bioactive silver in the human body. Such exposure creates the conditions for microbial resistance to develop.

E. coli bacteria. Photo: Flickr/NIAID

 

The use of silver as an antimicrobial agent dates back centuries. Its ability to destroy pathogens while seemingly having low toxicity on human cells has seen it widely employed, in treating burns or purifying water, for example. More recently, ultra-small (less than 10,000th of a millimetre) silver nanoparticles have been engineered for antimicrobial purposes.  Their commercial appeal lies in superior potency at lower concentrations than “bulk” silver.

“Nanosilver is a proven antimicrobial agent whose reliability is being jeopardised by the commercialisation of people’s fear of bacteria,” Dr Gunawan said.

“Our use of it needs to be far more judicious, in the same way we need to approach antibiotic usage. Nanosilver is a useful tool but we need to be careful, use it wisely and only when the benefit outweighs the risk.

“People need to be made aware of just how widely it is used, but more importantly they need to be made aware that the presence of nanosilver has been shown to cause antimicrobial resistance.”

What is also needed, Dr Gunawan said, is a targeted surveillance strategy to monitor for any occurrence of resistance.

Professor Harry said the findings were a significant contribution to addressing the global antimicrobial resistance crisis.

“This research emphasises the threat posed to our health and that of the environment by the inappropriate use of nanosilver as an antibacterial, particularly in ordinary household and consumer items,” she said.

Here’s a link to and a citation for the paper,

Widespread and Indiscriminate Nanosilver Use: Genuine Potential for Microbial Resistance by Cindy Gunawan, Christopher P. Marquis, Rose Amal, Georgios A. Sotiriou, Scott A. Rice⊥, and Elizabeth J. Harry. ACS Nano, Article ASAP DOI: 10.1021/acsnano.7b01166 Publication Date (Web): March 24, 2017

Copyright © 2017 American Chemical Society

This paper is behind a paywall.

Meanwhile, researchers at the University Calgary (Alberta, Canada) may have discovered what could cause resistance to silver.

Canada

This April 25, 2017 news release on EurekAlert is from the Experimental Biology Annual Meeting 2017,

Silver and other metals have been used to fight infections since ancient times. Today, researchers are using sophisticated techniques such as the gene-editing platform Crispr-Cas9 to take a closer look at precisely how silver poisons pathogenic microbes–and when it fails. The work is yielding new insights on how to create effective antimicrobials and avoid the pitfalls of antimicrobial resistance.

Joe Lemire, a postdoctoral fellow at the University of Calgary, will present his work in this area at the American Society for Biochemistry and Molecular Biology annual meeting during the Experimental Biology 2017 meeting, to be held April 22-26 in Chicago.

“Our overarching goal is to deliver the relevant scientific evidence that would aid policymakers in developing guidelines for when and how silver could be used in the clinic to combat and control infectious pathogens,” said Lemire. “With our enhanced mechanistic understanding of silver toxicity, we also aim to develop novel silver-based antimicrobial therapies, and potentially rejuvenate other antibiotic therapies that bacteria have come to resist, via silver-based co-treatment strategies.”

Lemire and his colleagues are using Crispr-Cas9 genome editing to screen for and delete genes that allow certain bacterial species to resist silver’s antimicrobial properties. [emphasis mine] Although previous methods allowed researchers to identify genes that confer antibiotic resistance or tolerance, Crispr-Cas9 is the first technology to allow researchers to cleanly delete these genes from the genome without leaving behind any biochemical markers or “scars.”

The team has discovered many biological pathways involved in silver toxicity and some surprising ways that bacteria avoid succumbing to silver poisoning, Lemire said. While silver is used to control bacteria in many clinical settings and has been incorporated into hundreds of commercial products, gaining a more complete understanding of silver’s antimicrobial properties is necessary if we are to make the most of this ancient remedy for years to come.

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Joe Lemire will present this research at 12-2:30 p.m. Tuesday, April 25, [2017] in Hall F, McCormick Place Convention Center (poster B379 939.2) (abstract). Contact the media team for more information or to obtain a free press pass to attend the meeting.

About Experimental Biology 2017

Experimental Biology is an annual meeting comprised of more than 14,000 scientists and exhibitors from six host societies and multiple guest societies. With a mission to share the newest scientific concepts and research findings shaping clinical advances, the meeting offers an unparalleled opportunity for exchange among scientists from across the U.S. and the world who represent dozens of scientific areas, from laboratory to translational to clinical research. http://www.experimentalbiology.org #expbio

About the American Society for Biochemistry and Molecular Biology (ASBMB)

ASBMB is a nonprofit scientific and educational organization with more than 12,000 members worldwide. Founded in 1906 to advance the science of biochemistry and molecular biology, the society publishes three peer-reviewed journals, advocates for funding of basic research and education, supports science education at all levels, and promotes the diversity of individuals entering the scientific workforce. http://www.asbmb.org

Lemire’s co-authors for the work presented at the 2017 annual meeting are: Kate Chatfield-Reed (The University of Calgary), Lindsay Kalan (Perelman School of Medicine), Natalie Gugala (The University of Calgary), Connor Westersund (The University of Calgary), Henrik Almblad (The University of Calgary), Gordon Chua (The University of Calgary), Raymond Turner (The University of Calgary).

For anyone who wants to pursue this research a little further, the most recent paper I can find is this one from 2015,

Silver oxynitrate: An Unexplored Silver Compound with Antimicrobial and Antibiofilm Activity by Joe A. Lemire, Lindsay Kalan, Alexandru Bradu, and Raymond J. Turner. Antimicrobial Agents and Chemotherapy 05177-14, doi: 10.1128/AAC.05177-14 Accepted manuscript posted online 27 April 2015

This paper appears to be open access.