“If you look at the history, no one’s really discovered a fundamentally new class of antibiotic for the past 40 to 50 years,” said IU chemist Michael VanNieuwenhze, who led the study. “Antibiotic resistance is a significant and urgent public health threat, and we think that new ways to address it — including this — have significant value.”

The need for new ways to study bacteria is driven in large part by the threat of bacterial resistance. According to the Centers for Disease Control and Prevention, at least 2 million people in the U.S. get an antibiotic-resistant infection each year, and at least 23,000 people die.

“This new technology takes advantages of specific cellular enzymes to stick colored dyes — or ‘probes’ — into the walls of bacterial cells,” VanNieuwenhze said. “Since these same enzymes are inhibited by other well-known antibacterial compounds — most notably, penicillin — we could theoretically also use these probes to seek out entirely new classes of drugs that inhibit the same reaction.”

VanNieuwenhze’s lab has already created two other cellular probes patented through IU — called FDAAs (fluorescent D-amino acids) and DAADs (d-amino acid dipeptides) — which are in use in laboratories across the globe. Their new class of probes, which build upon these earlier advances, are called rotor-fluorogenic D-amino acids, or RfDAAs. IU has also filed for a patent on this technology.

The main advantage of RfDAAs is their ease of use and ability to show cellular activity in real time.This is because the probes don’t require washing steps to remove unincorporated chemicals that blur the distinct boundaries between bacterial cells and their surrounding environment.

Instead, RfDAAs only light up when they’re integrated into bacteria’s cell walls as part of the regular growth process. The probes illuminate cell walls faster and clearer without the steps that can stop cellular activity.

It’s the difference between a snapshot and a video, VanNieuwenhze said. A video provides much more information about how cell walls grow, change and interact with their environment. Video: https://news.iu.edu/doc/2019-02-25-rfdaas-in-action.mp4

Already, VanNieuwenhze has launched a collaboration with IU School of Medicine to apply these methods to the search for new inhibitors of bacterial cell wall synthesis, and the probes are also in use to study bacterial cell division, which may unveil new targets for antibiotic discovery. In addition, the biotechnology company ThermoFisher Scientific recently purchased exclusive rights to market the two earlier probes as commercial products; other industrial groups have reached out about applying the technology to high-throughput screens designed to identify new drug leads.

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The resilient fibers, the team discovered, respond very strongly to changes in humidity. Above a certain level of relative humidity in the air, they suddenly contract and twist, exerting enough force to potentially be competitive with other materials being explored as actuators — devices that move to perform some activity such as controlling a valve.

The findings are being reported today in the journal Science Advances, in a paper by MIT Professor Markus Buehler, head of the Department of Civil and Environmental Engineering, along with former postdoc Anna Tarakanova and undergraduate student Claire Hsu at MIT; Dabiao Liu, an associate professor at Huazhong University of Science and Technology in Wuhan, China; and six others.

Researchers recently discovered a property of spider silk called supercontraction, in which the slender fibers can suddenly shrink in response to changes in moisture. The new finding is that not only do the threads contract, they also twist at the same time, providing a strong torsional force. “It’s a new phenomenon,” Buehler says.

“We found this by accident initially,” Liu says. “My colleagues and I wanted to study the influence of humidity on spider dragline silk.” To do so, they suspended a weight from the silk to make a kind of pendulum, and enclosed it in a chamber where they could control the relative humidity inside. “When we increased the humidity, the pendulum started to rotate. It was out of our expectation. It really shocked me.”

The team tested a number of other materials, including human hair, but found no such twisting motions in the others they tried. But Liu said he started thinking right away that this phenomenon “might be used for artificial muscles.”

“This could be very interesting for the robotics community,” Buehler says, as a novel way of controlling certain kinds of sensors or control devices. “It’s very precise in how you can control these motions by controlling the humidity.”

Spider silk is already known for its exceptional strength-to-weight ratio, its flexibility, and its toughness, or resilience. A number of teams around the world are working to replicate these properties in a synthetic version of the protein-based fiber.

While the purpose of this twisting force, from the spider’s point of view, is unknown, researchers think the supercontraction in response to moisture may be a way to make sure a web is pulled tight in response to morning dew, perhaps protecting it from damage and maximizing its responsiveness to vibration for the spider to sense its prey.

“We haven’t found any biological significance” for the twisting motion, Buehler says. But through a combination of lab experiments and molecular modeling by computer, they have been able to determine how the twisting mechanism works. It turns out to be based on the folding of a particular kind of protein building block, called proline.

Investigating that underlying mechanism required detailed molecular modeling, which was carried out by Tarakanova and Hsu. “We tried to find a molecular mechanism for what our collaborators were finding in the lab,” Hsu explains. “And we actually found a potential mechanism,” based on the proline. They showed that with this particular proline structure in place, the twisting always occurred in the simulations, but without it there was no twisting.

“Spider dragline silk is a protein fiber,” Liu explains. “It’s made of two main proteins, called MaSp1 and MaSp2.” The proline, crucial to the twisting reaction, is found within MaSp2, and when water molecules interact with it they disrupt its hydrogen bonds in an asymmetrical way that causes the rotation. The rotation only goes in one direction, and it takes place at a threshold of about 70 percent relative humidity.

“The protein has a rotational symmetry built in,” Buehler says. And through its torsional force, it makes possible “a whole new class of materials.” Now that this property has been found, he suggests, maybe it can be replicated in a synthetic material. “Maybe we can make a new polymer material that would replicate this behavior,” Buehler says.

“Silk’s unique propensity to undergo supercontraction and exhibit a torsional behavior in response to external triggers such as humidity can be exploited to design responsive silk-based materials that can be precisely tuned at the nanoscale,” says Tarakanova, who is now an assistant professor at the University of Connecticut. “Potential applications are diverse: from humidity-driven soft robots and sensors, to smart textiles and green energy generators.”

It may also turn out that other natural materials exhibit this property, but if so this hasn’t been noticed. “This kind of twisting motion might be found in other materials that we haven’t looked at yet,” Buehler says. In addition to possible artificial muscles, the finding could also lead to precise sensors for humidity.

Now, researchers at The University of Tokyo Institute of Industrial Science have shown that the structure of a particular class of liquids and amorphous materials, known as tetrahedral glass formers, can be understood from experimental measurements. Their findings were published in Science Advances.

When a crystalline material scatters X-rays or neutrons, it produces a well-defined pattern as a result of its structure. In contrast, the patterns produced by liquids and amorphous materials show broad peaks that do not provide the same degree of information. However, liquids and amorphous materials that have a tendency to form a network, such as silica and silicon, are known to exhibit a feature called the first sharp diffraction peak (FSDP).

Many theories linking the properties of the FSDP to the structure of the related material have been presented; however, there is still no accepted consensus on what gives rise to these features. Now researchers have demonstrated that the FSDP is a result of the tetrahedral nature of the local ordering of atoms in the liquid.

“The covalent nature of the bonding in the liquids we studied results in a certain degree of organization on a local level, although the order does not extend over a long range,” study corresponding author Hajime Tanaka explains. “We focused on the tetrahedral unit structure that forms in the materials, and as a result have established a model that is able to support a range of experimental findings.”

The researchers tested their tetrahedron model using simulated and experimental data for numerous oxide, halide, chalcogenide, and monoatomic materials in the liquid or amorphous states. The findings were able to explain the origin of the FSDP as well as other higher wavenumber peaks and features.

“We have shown direct evidence of a two-state structure in which order and disorder coexist in the same network forming liquid,” First author Rui Shi explains. “We hope that our findings will lead to an improved understanding of the properties of tetrahedral liquids and glasses, and consequently have an impact on areas such as earth science and semiconductor materials.”

The direct link between data that can be acquired using standard techniques and quantitative structural information on the degree and range of local order demonstrates the practical significance and potential of the presented model.

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“Amphibians inhabit humid places favoring the growth of fungi, coexisting with these and other microorganisms in their environment, some of which can be pathogenic,” said Smithsonian scientist Roberto Ibáñez, one of the authors of the study published in Scientific Reports. “As a result of evolution, amphibians are expected to possess chemical compounds that can inhibit the growth of pathogenic bacteria and fungi.”

The team first travelled to the Chiriquí highlands in Panama, where the chytrid fungus, responsible for the disease chytridiomycosis, has severely affected amphibian populations. They collected samples from seven frog species to find out what kind of skin bacteria they harbored.

“Amphibians have glands scattered on their skin that produce different compounds,” Ibáñez said. “In addition, their skin is inhabited by a diverse community of bacteria that produce metabolites that inhibit the growth of fungi and other bacteria.”

Back in the laboratory, 201 bacterial strains were retrieved from their samples and tested against Aspergillus fumigatus, a fungus that causes invasive aspergillosis in immunocompromised patients. Of these, 29 showed antifungal activity, but one in particular caught their attention: a bacterium called Pseudomonas cichorii. This one showed the greatest potential to inhibit the growth of A. fumigatus.

After identifying the most promising bacteria, the scientists had a new question: among all the chemical compounds produced by P. cichorii, which one was keeping the fungi at bay? To find out, they used mass spectrometry and molecular networking techniques. They also observed the interactions between this bacteria and A. fumigatus to identify the bacterial compounds acting in areas where fungal activity was most inhibited. The main compounds were cyclic lipopeptides that included massetolides and viscosin.

The team then separated viscosin from the other components produced by P. cichorii and tested it invitro against A. fumigatus and the chytrid fungus. The results confirmed that viscosin displayed significant activity against both.

This research project holds promise for humans and frogs. Studying the skin bacteria of Panamanian frogs may lead to the development of alternative drugs to treat the fungi causing aspergillosis in humans, which are becoming more drug-resistant, and to defy the chytridiomycosis epidemic, the major source of disease-related death among amphibians worldwide.

“We are showing to the scientific community a set of possible alternative molecules to fight fungal drug resistance in humans,” said Christian Martin, the first author of the study along with the principal investigator Marcelino Gutiérrez, both from INDICASAT. “Although more studies are needed, our collaboration could spark interest in the conservation of amphibians as a novel source of bioactive compounds in humans. For amphibians, this is a promising study because there are only four bacterial secondary metabolites chemically described that inhibit chytrid fungi. In this study, we are introducing a new family of chemical compounds found in Panamanian frogs that could help amphibians worldwide.”

“I consider that bioprospecting compounds from skin secretions or bacteria living in frog’s skins is just beginning,” Ibáñez said. “This research has identified an antifungal compound produced by frog skin bacteria, which may be used to control pathogenic fungi affecting humans and amphibians. More research will be required to determine its potential medicinal use.”

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