Now researchers report in Nature Nanotechnology that magnetism can also behave in surprising ways under these conditions. In twisted antiferromagnetic layers, magnetic spin patterns are not limited to the small repeating moiré unit cell. Instead, they can spread into much larger, topological structures that extend across hundreds of nanometers.

Giant Magnetic Textures Beyond the Moiré Pattern

In most moiré systems, the size of physical effects is determined directly by the interference pattern created when two crystal lattices overlap. Magnetic order in stacked van der Waals magnets was widely expected to follow this same length scale. The new findings challenge that assumption.

The team examined twisted double bilayer chromium triiodide (CrI₃) using scanning nitrogen-vacancy magnetometry, a technique that images magnetic fields with nanoscale precision. They observed magnetic textures reaching distances of up to ~300 nm, far exceeding the size of a single moiré cell and roughly ten times larger than the underlying wavelength.

A Counterintuitive Twist Angle Effect

The results reveal an unexpected pattern. When the twist angle becomes smaller, the moiré wavelength increases. However, the magnetic textures do not simply grow along with it. Instead, their size changes in the opposite way, reaching a maximum near 1.1° and disappearing above ~2°.

This reversal shows that magnetism is not just copying the moiré template. Rather, it arises from a balance between several competing forces, including exchange interactions, magnetic anisotropy and Dzyaloshinskii-Moriya interactions. All of these are subtly adjusted by how the layers are rotated relative to one another. Large scale spin dynamics simulations back up this interpretation, demonstrating the formation of extended Néel-type antiferromagnetic skyrmions that span multiple moiré cells.

Skyrmions and Low Power Spintronics

These findings matter beyond basic physics. Skyrmions are promising for future information technologies because they are small, stable and protected by their topology. They can also be moved using very little energy. Creating them simply by adjusting the twist angle, without lithography, heavy metals or strong electric currents, provides a clean and geometry driven path toward low power spintronic devices.

The researchers describe this phenomenon as super-moiré spin order, highlighting that twist engineering operates across multiple scales. A change in atomic alignment can generate topological structures on much larger, mesoscale distances. This challenges the long held idea that moiré physics is only a local effect and positions twist angle as a powerful thermodynamic control parameter capable of tuning exchange, anisotropy and chiral interactions to stabilize topological phases.

From a practical standpoint, these large and robust Néel-type skyrmionic textures are well suited for integration into devices. Their larger size makes them easier to detect and manipulate. At the same time, their topological protection and insulating host material suggest extremely low energy loss during operation. As scientists continue to explore how geometry shapes quantum behavior, such emergent magnetic states could play an important role in developing energy efficient, post-CMOS computing technologies.

Dr. Elton Santos, Reader in Theoretical/Computational Condensed Matter Physics, University of Edinburgh, whose team led the modelling aspect of the project, said: “This discovery shows that twisting is not just an electronic knob, but a magnetic one. We’re seeing collective spin order self-organize on scales far larger than the moiré lattice. It opens the door to designing topological magnetic states simply by controlling angle, which is a remarkably simple handle with profound practical consequences.”

The findings were detailed in the journal Geology by a research team led by Álvaro Penteado Crósta, a geologist and senior professor at the Institute of Geosciences at the State University of Campinas (IG-UNICAMP). The project involved collaborators from Brazil, Europe, the Middle East, and Australia.

Before this discovery, only five major tektite fields were known worldwide, located in Australasia, Central Europe, the Ivory Coast, North America, and Belize. The Brazilian field now joins this rare group.

A 900 Kilometer Strewn Field of Impact Glass

The geraisites were first documented in three municipalities in northern Minas Gerais — Taiobeiras, Curral de Dentro, and São João do Paraíso — across an area about 90 kilometers long. After the study was submitted, additional finds were reported in Bahia and later in Piauí. As a result, the total known distribution now stretches more than 900 kilometers.

“This growth in the area of occurrence is entirely consistent with what is observed in other tektite fields around the world. The size of the field depends directly on the energy of the impact, among other factors,” Crósta explains.

By July 2025, researchers had collected about 500 pieces. With more recent discoveries, that total now exceeds 600. The fragments vary widely in size, from less than 1 gram to 85.4 grams, and can measure up to 5 centimeters along their longest dimension. Their forms match the aerodynamic shapes typical of tektites, including spheres, ellipsoids, droplets, disks, dumbbells, and twisted shapes.

What the Geraisites Look Like

At first glance, the geraisites appear black and opaque. Under strong light, however, they become translucent with a grayish green hue. This shade differs from the brighter green moldavites of Europe, which have been used in jewelry since the Middle Ages. The surfaces of the Brazilian specimens are pitted with small cavities.

“These small cavities are traces of gas bubbles that escaped during the rapid cooling of the molten material as it traveled through the atmosphere, a process also observed in volcanic lava but especially characteristic of tektites,” says Crósta.

Chemical Clues Confirm Impact Origin

Laboratory analysis shows that the geraisites contain high levels of silica (SiO2), ranging from 70.3% to 73.7%. Sodium (Na2O) and potassium (K2O) oxides together account for 5.86% to 8.01%, slightly higher than what is seen in other tektite regions. Trace elements such as chromium (10-48 parts per million) and nickel (9-63 ppm) vary in small amounts, suggesting the original target rock was not uniform. Researchers also detected rare inclusions of lechatelierite, a high temperature glassy silica that forms during extreme heating, further confirming an impact origin.

“One of the decisive criteria for classifying the material as a tektite was its very low water content, as measured by infrared spectroscopy: between 71 and 107 ppm. For comparison, volcanic glasses, such as obsidian, usually contain from 700 ppm to 2% water, whereas tektites are notoriously much drier,” Crósta points out.

Dating the Ancient Asteroid Impact

Argon isotope dating (⁴⁰Ar/³⁹Ar) indicates the impact occurred around 6.3 million years ago, near the end of the Miocene epoch. Three closely grouped age results were obtained (6.78 ± 0.02 Ma, 6.40 ± 0.02 Ma, and 6.33 ± 0.02 Ma), supporting the conclusion that they came from a single event.

“The age of 6.3 million years should be interpreted as a maximum age since some of the argon may have been inherited from the ancient rocks targeted by the impact,” the researcher comments.

The Search for a Missing Crater

No crater linked to the impact has yet been identified. According to Crósta, this is not unusual. Only three of the six major classical tektite fields have confirmed craters. In the case of the vast Australasia field, the crater is thought to lie beneath the ocean.

Isotopic geochemistry suggests the molten material came from Archean continental crust dating between 3.0 and 3.3 billion years old. That evidence points to the São Francisco craton, one of the oldest and most stable regions of South America’s continental crust.

“The isotopic signature indicates a very ancient continental, granitic source rock. This greatly reduces the universe of candidate areas,” says Crósta.

Future surveys using magnetic and gravimetric techniques could detect circular underground structures that mark a buried or eroded crater.

Estimating the Size of the Impact

Researchers cannot yet determine the exact size of the object that struck Earth, but they believe it was not small. The volume of melted rock and the broad distribution of debris indicate a powerful event, though likely less intense than the impact that created the enormous Australasia field, which spans thousands of kilometers.

The team is developing mathematical models to estimate the impact’s energy, entry speed, trajectory angle, and total volume of melted material. These calculations will become more refined as additional data on the distribution of geraisites are gathered.

The discovery adds an important chapter to South America’s impact history. Only about nine large impact structures are currently known on the continent, most of them much older and located in Brazil. The findings also suggest that tektites may be more widespread than previously recognized, but are sometimes overlooked or mistaken for ordinary glass.

Separating Science From Speculation

To address exaggerated claims about asteroid threats, Crósta works with undergraduate students to manage the Instagram account @defesaplanetaria. The page focuses on science communication and aims to distinguish genuine risks from unfounded speculation about meteorites and asteroids.

Impacts were common in the early solar system, when debris was abundant and planetary orbits were unstable. Large bodies shifted positions, sending smaller objects in many directions. Today, the solar system is far more stable, and major impacts are much less frequent.

“Understanding these processes is essential to separating science from speculation,” the researcher concludes.

Crósta has studied meteorite impact structures since his master’s research project in 1978. Over the years, he has received several grants from FAPESP (08/53588-7, 12/50368-1, and 12/51318-8).

To make the product, the team used honey from native bees as a natural, edible solvent to draw out beneficial compounds from cocoa shells, a byproduct typically discarded during chocolate production. These compounds include theobromine and caffeine, which are linked to heart health. The ultrasound-assisted process also boosted the honey’s levels of phenolic compounds, known for their antioxidant and anti-inflammatory effects.

Researchers who sampled the mixture report a pronounced chocolate flavor that varies depending on the proportion of honey to cocoa shells. Additional testing is planned to further evaluate taste and other sensory characteristics.

“Of course, the biggest appeal to the public is the flavor, but our analyses have shown that it has a number of bioactive compounds that make it quite interesting from a nutritional and cosmetic point of view,” says Felipe Sanchez Bragagnolo, the study’s first author. He carried out the research during his postdoctoral work at the Faculty of Applied Sciences (FCA) at UNICAMP in Limeira with support from FAPESP.

Working with INOVA UNICAMP, the university’s innovation agency, the team is now seeking a commercial partner to license the patented method and bring the product to market (read more at agencia.fapesp.br/52969).

Native Bee Honey and Biodiversity

Beyond reducing food waste, the project highlights the sustainable use of local biodiversity. Honey from native Brazilian bees was selected because it generally contains more water and is less viscous than honey from European bees (Apis mellifera), making it more effective for extracting compounds.

The researchers tested honey from five Brazilian species: borá (Tetragona clavipes), jataí (Tetragonisca angustula), mandaçaia (Melipona quadrifasciata), mandaguari (Scaptotrigona postica), and moça-branca (Frieseomelitta varia). Cocoa shells were supplied by the São Paulo State Department of Agriculture and Supply’s Comprehensive Technical Assistance Coordination Office (CATI) unit in São José do Rio Preto.

Mandaguari honey was initially used to refine the extraction process because its water content and viscosity were moderate compared to the others. Once optimized, the same procedure was applied to the remaining honey varieties.

Bragagnolo notes that honey is sensitive to environmental factors such as climate, storage, and temperature. “Therefore, it’s possible to adapt the process to locally available honey, not necessarily mandaguari honey,” he says.

Green Chemistry and Ultrasound Extraction

The extraction method relies on ultrasound technology. A probe that resembles a metal pen is inserted into a container holding the honey and cocoa shells. Sound waves generated by the probe help release compounds from the plant material so they dissolve into the honey.

This approach works by forming microscopic bubbles that collapse and briefly raise the temperature, helping break down the shells. In the food industry, ultrasound-assisted extraction is viewed as an environmentally friendly technique because it is faster and more efficient than many conventional methods.

Sustainability was formally evaluated in the study using Path2Green software, developed by a team led by Professor Mauricio Ariel Rostagno of FCA-UNICAMP, who also supervised Bragagnolo’s postdoctoral research and coordinated the project. The analysis measured how well the process aligned with 12 principles of green chemistry, including transportation, post-treatment, purification, and application. The use of a local, edible, ready-to-use solvent was a major advantage. On a scale of -1 to +1, the product received a score of +0.118.

“We believe that with a device like this, in a cooperative or small business that already works with both cocoa and native bee honey, it’d be possible to increase the portfolio with a value-added product, including for haute cuisine,” Rostagno suggests.

Shelf Life and Future Applications

The team is also planning studies to examine how ultrasound affects honey microbiology. Just as it breaks down plant cells, ultrasound can disrupt the cell walls of microorganisms such as bacteria that may spoil the product.

“Honey from native bees usually needs to be refrigerated, matured, dehumidified, or pasteurized, unlike honey from European bees, which can be stored at room temperature. We suspect that, simply by being exposed to ultrasound, the microorganisms contained in the honey are eliminated, increasing the stability and shelf life of the product,” he explains.

Looking ahead, the researchers intend to explore other uses for native bee honey as a solvent in ultrasound-assisted extraction, including processing additional plant residues.

Along with postdoctoral fellowships and an international research internship for Bragagnolo, the project received multiple scholarships and grants from FAPESP (23/02064-8, 23/16744-0, 21/12264-9, 20/08421-9, 19/13496-0, and 18/14582-5.

Using an advanced light based imaging method combined with machine learning, the team examined brain tissue from both healthy and Alzheimer’s affected animals. Their results, published in ACS Applied Materials and Interfaces, reveal that chemical changes linked to Alzheimer’s are not confined to amyloid plaques. Instead, these alterations appear throughout the brain in uneven and complex patterns.

Laser Imaging Reveals Brain Chemistry in Detail

To detect these subtle shifts, the scientists turned to hyperspectral Raman imaging. This sophisticated form of Raman spectroscopy uses a laser to detect the unique chemical fingerprints of molecules within tissue.

“Traditional Raman spectroscopy takes one measurement of chemical information per molecular site,” said Ziyang Wang, an electrical and computer engineering doctoral student at Rice who is a first author on the study. “Hyperspectral Raman imaging repeats this measurement thousands of times across an entire tissue slice to build a full map. The result is a detailed picture showing how chemical composition varies across different regions of the brain.”

The researchers scanned entire brains slice by slice, compiling thousands of overlapping measurements to build high resolution molecular maps of both healthy and diseased tissue. Because the imaging was label free, the samples were not treated with dyes, fluorescent proteins or molecular tags.

“This means we observed the brain as is, capturing a complete, unaltered portrait of its chemical makeup,” Wang said. “I think this makes the approach more unbiased and better suited for discovering new disease-related changes that might otherwise be missed.”

Machine Learning Maps Uneven Alzheimer’s Damage

The imaging process generated enormous amounts of data, which the team analyzed using machine learning (ML). They first applied unsupervised ML, allowing algorithms to detect natural patterns in the chemical signals without prior assumptions. These models sorted tissue based entirely on its molecular characteristics. The researchers then used supervised ML, training models to distinguish between Alzheimer’s and non Alzheimer’s samples. This step helped determine how strongly different brain regions reflected Alzheimer’s related chemistry.

“We found that the changes caused by Alzheimer’s disease are not spread evenly across the brain,” Wang said. “Some regions show strong chemical changes, while others are less affected. This uneven pattern helps explain why symptoms appear gradually and why treatments that focus on only one problem have had limited success.”

Metabolic Disruption in Memory Regions

Beyond protein buildup, the study identified broader metabolic differences between healthy and Alzheimer’s brains. Levels of cholesterol and glycogen varied across regions, with the most dramatic contrasts appearing in areas responsible for memory, particularly the hippocampus and cortex.

“Cholesterol is important for maintaining brain cell structure, and glycogen serves as a local energy reserve,” said Shengxi Huang, associate professor of electrical and computer engineering and materials science and nanoengineering and corresponding author on the study. “Together, these findings support the idea that Alzheimer’s involves broader disruptions in brain structure and energy balance, not only protein buildup and misfolding,” added Huang, who is also a member of the Ken Kennedy Institute, the Rice Advanced Materials Institute and the Smalley-Curl Institute.

A Broader View of Alzheimer’s Progression

The project grew out of ongoing discussions about new ways to study the Alzheimer’s brain.

“At first, we were measuring only small areas of brain tissue,” Wang said. “Then I thought, what if we could map the entire brain and gain a much broader view? It took several rounds of testing and trial and error before the measurements and analysis worked well together.”

When the complete chemical map finally came together, the impact was immediate.

“Patterns emerged that had not been visible under regular imaging,” Wang said. “Seeing those results was deeply satisfying. It felt like revealing a hidden layer of information that had been there all along, waiting for the right way to be analyzed.”

By delivering the first detailed, dye free chemical maps of the Alzheimer’s brain, this research offers a more comprehensive view of the disease. The team hopes the findings will eventually support earlier diagnosis and more effective strategies to slow progression.

The research was supported by the National Science Foundation (2246564, 1934977), the National Institutes of Health (1R01AG077016) and the Welch Foundation (C2144).

A new study published in Science offers an unprecedented look at that process. Researchers at The Rockefeller University built the most detailed atlas so far of how aging affects thousands of cell subtypes across 21 mammalian tissues. By examining nearly 7 million individual cells from mice at three different ages, the team identified which cells are most vulnerable over time and what factors may be driving their decline.

“Our goal was to understand not just what changes with aging, but why,” says Junyue Cao, who heads the Laboratory of Single Cell Genomics and Population Dynamics. “By mapping both cellular and molecular changes, we can identify what drives aging. That opens the door to interventions that target the aging process itself.”

One of the most striking findings was that many age-related shifts happen in sync across multiple organs. The researchers also found that nearly half of these changes differ between males and females.

A Massive Cellular Census Across 21 Organs

To map aging at this scale, Cao’s team, led by graduate student Ziyu Lu, refined a method known as single-cell ATAC-seq. This approach looks at how DNA is packaged inside each cell, revealing which regions of the genome are accessible and active, a key indicator of a cell’s state and function.

The researchers applied this technique to millions of individual cells taken from 21 organs in 32 mice at three ages: one month (young adult), five months (middle-aged), and 21 months (elderly).

“What’s remarkable is that this entire atlas was generated by a single graduate student,” Cao says. “Most large atlases like this require large consortia with dozens of laboratories but our method is far more efficient than other approaches.”

In total, the lab identified more than 1,800 distinct cell subtypes, including many rare groups that had never been fully described. The team then tracked how the numbers of these cells changed as the mice moved from young adulthood to middle age and then to old age.

Early and Coordinated Cellular Shifts

For decades, scientists believed aging mainly altered how cells function, not how many of each type exist. This new analysis challenges that view. About one quarter of all cell types showed significant changes in abundance over time. Certain muscle and kidney cell populations declined sharply, while immune cells expanded considerably.

“The system is far more dynamic than we realized,” says Cao. “And some of these changes begin surprisingly early. By five months of age, some cell populations had already begun to decline. This tells us that aging isn’t just something that happens late in life; it’s a continuation of ongoing developmental processes.”

Equally surprising was how synchronized these changes were. Similar cellular states rose and fell together across different organs. This pattern suggests that shared signals, possibly factors circulating in the bloodstream, help coordinate aging throughout the body.

The study also revealed pronounced differences between males and females. Roughly 40 percent of aging-associated changes varied significantly by sex. For example, females showed much broader immune activation as they aged.

“It’s possible this could explain the higher prevalence of autoimmune diseases in women,” Cao speculates.

Genetic Hotspots and Future Anti-Aging Therapies

Beyond counting how cell populations shifted, the researchers examined how accessible regions of DNA changed within those cells over time. Out of 1.3 million genomic regions analyzed, about 300,000 displayed significant aging-related alterations. Around 1,000 of those changes appeared across many different cell types, reinforcing the idea that common biological programs drive aging across the body. Many of these shared regions were linked to immune function, inflammation, or stem cell maintenance.

“This challenges the idea that aging is just random genomic decay,” Cao says. “Instead, we see specific regulatory hotspots that are particularly vulnerable, and these are precisely the regions we should be studying if we want to understand what drives the aging process.”

When the team compared their findings with earlier research, they discovered that immune signaling molecules called cytokines can trigger many of the same cellular changes observed during aging. Cao suggests that drugs designed to adjust these cytokines could potentially slow coordinated aging processes across multiple organs.

“This is really a starting point,” Cao says. “We’ve identified the vulnerable cell types and molecular hotspots. Now the question is whether we can develop interventions that target these specific aging processes. Our lab is already working on that next step.”

The full aging atlas is available to the public at epiage.net.

But new evidence suggests that expectation may not be accurate.

In what the team calls the most precise measurement so far of iron flowing from an Antarctic glacier, scientists from Rutgers University-New Brunswick found that meltwater from an ice shelf contributes far less iron to surrounding ocean waters than previously believed.

The study, published in Communications Earth and Environment, raises new questions about where iron in the Southern Ocean actually originates. According to the researchers, the results could influence how climate change forecasts and models are developed.

“It has been widely assumed that glacial melting underneath ice shelves contributes considerable bioavailable iron to these shelf waters, in a process of natural glacier-driven iron fertilization,” said Rob Sherrell, a professor in the Department of Marine and Coastal Sciences at the Rutgers School of Environmental and Biological Sciences and the study’s principal investigator.

Sherrell said the findings revise those assumptions. The amount of iron carried by meltwater is several times lower than earlier estimates. In addition, much of that iron appears to come from a different form of meltwater than the kind produced directly by melting ice shelves.

Why Iron in the Southern Ocean Matters

Even though Antarctic waters are dark for months at a time, the Southern Ocean supports abundant phytoplankton growth. These microscopic plants form the foundation of the food web, feeding krill that sustain penguins, seals, and whales. As phytoplankton grow, they remove large quantities of carbon dioxide from the atmosphere through photosynthesis, making this region the world’s largest oceanic sink for the climate warming gas.

Until now, much of what scientists understood about iron sources in these waters came from simulations and computer models. Sherrell and colleagues from Rutgers and partner institutions in the United States and the United Kingdom chose to gather direct field measurements instead.

In 2022, the researchers traveled aboard the now-decommissioned U.S. icebreaker, the Nathaniel B. Palmer, to the Dotson Ice Shelf in the Amundsen Sea of West Antarctica. The Amundsen Sea accounts for most of the sea level rise driven by Antarctic melting. Their goal was to collect glacial meltwater at its source.

Sampling Beneath the Ice Shelf

In the Amundsen Sea, meltwater forms under floating ice shelves, which extend from glaciers on land into the ocean. The melting is driven mainly by relatively warm water from the deep ocean that flows into cavities beneath the ice.

At the Dotson Ice Shelf, the team located where seawater flows into one of these cavities and where it exits after mixing with meltwater. Water samples were taken at both entry and exit points.

Back in New Jersey, Venkatesh Chinni, a postdoctoral scholar and lead author of the study, measured iron concentrations in the samples, analyzing both dissolved iron and iron attached to suspended particles. Collaborators Jessica Fitzsimmons and Janelle Steffen at Texas A&M University examined isotopic ratios to “fingerprint” the iron and trace its origin. Steffen performed the initial isotopic analyses in the laboratory of Tim Conway at the University of South Florida.

Using these measurements, Chinni and the team calculated how much additional iron was present in water leaving the cavity compared with water entering it. The isotopic signatures also helped identify which melting processes were responsible.

Deep Water and Sediments Supply Most Iron

The results were unexpected, Sherrell said. Meltwater accounted for only about 10% of the dissolved iron flowing out of the cavity. Most of the iron came from deep ocean water (62%), while another 28% originated from sediments on the continental shelf.

“Roughly 90% of the dissolved iron coming out of the ice shelf cavity comes from deep waters and sediments outside the cavity, not from meltwater,” Chinni said.

The isotope data also point to processes occurring beneath the glacier itself. The samples suggest the presence of a liquid meltwater layer that lacks dissolved oxygen. Under such conditions, solid iron oxides in bedrock can dissolve more readily, releasing iron into the water. According to Chinni, this mechanism may contribute more iron than melting ice shelves do.

Rethinking Antarctic Iron and Climate Models

Together, these findings challenge long standing assumptions about iron sources in the Southern Ocean as the planet warms. The researchers emphasize that more work is needed to fully understand how subglacial processes influence iron release.

“Our claim in this paper is that the meltwater itself carries very little iron, and that most of the iron that it does carry comes from the grinding up and dissolving of bedrock into the liquid layer between the bedrock and the ice sheet, not from the ice that is driving sea level rise,” Sherrell said.

He added that many scientists may find this conclusion surprising.

The findings appear in the February 26 issue of Nature. The research was led by Yancheng Evelyn Li, a graduate student in the lab of Bil Clemons at Caltech. Clemons, the Arthur and Marian Hanisch Memorial Professor of Biochemistry, is the corresponding author.

The Urgent Need for New Antibiotics

Bacteria evolve quickly, and that adaptability is fueling a growing public health crisis. As Clemons explains, “Evolution is powerful, and in bacteria, resistance to antibiotics develops quickly. This means that we now deal with bacteria that are resistant to all the medicines that we have.” He adds, “In the USA alone, tens of thousands of people die every year from antibiotic-resistant bacterial infections, and that number is rising rapidly. We need new antibiotics to combat this.”

With existing drugs losing effectiveness, researchers are searching for entirely new bacterial weak points.

Targeting the Bacterial Cell Wall

One long standing focus has been the pathway bacteria use to construct peptidoglycan, the rigid material that forms their cell wall. This process, called the peptidoglycan biosynthesis pathway, is especially attractive because peptidoglycan is found in bacteria but not in human cells. As Clemons notes, “Peptidoglycan is a unique feature of bacteria, and that makes it an attractive antibiotic target.”

Several antibiotics already disrupt this pathway. Penicillin, discovered by Alexander Fleming in the mid 20th century, blocks a late stage of peptidoglycan production. Related drugs such as amoxicillin work in a similar way.

Key Proteins MraY, MurG, and MurJ

Three essential proteins drive the movement of peptidoglycan building blocks across the bacterial inner membrane: MraY, MurG, and MurJ. These proteins help transport the components needed to assemble the cell wall outside the inner membrane barrier. If any one of them fails, peptidoglycan cannot be produced and the bacterium dies, making them promising drug targets.

Although researchers understand much about how these proteins function, Clemons points out that important mechanistic details remain unclear.

At present, no approved drugs directly inhibit these three proteins. Still, Clemons says there is potential. “We do know that we can find small molecules, either derived from nature or synthesized in chemical libraries, that will inhibit these proteins. Excitingly, recent discoveries have shown that bacteriophages have figured out how to target this pathway.”

How Bacteriophages Break Through Bacterial Defenses

Bacteriophages, or phages, are viruses that infect bacteria. To survive, they must enter a bacterial cell, replicate, and then escape to infect others. Breaking out requires getting through the peptidoglycan layer. Clemons explains, “Getting back out means that they have to get past the peptidoglycan layer. Because it acts like chainmail, the phages get stuck if they can’t break through it.”

The Clemons lab studies small phages that contain single stranded DNA or RNA. These viruses have compact genomes and rely on simple strategies to kill bacteria. In 2023, the team reported in Science on φX174, a phage with a long research history at Caltech.

Viral Proteins That Disable MurJ

Small phages rely on specialized protein antibiotics called single-gene lysis proteins, or Sgls (pronounced like “sigils”), to kill bacteria. Li and Clemons have focused on Sgls that target MurJ, one of the key cell wall proteins.

MurJ acts as a flippase. It transports peptidoglycan precursors from the inside of the cell across the membrane so they can be incorporated into the growing cell wall. Earlier work from collaborators showed that two unrelated Sgls, SglM and SglPP7, both kill bacteria by blocking MurJ.

To understand how this happens, Li used cryo electron microscopy at Caltech’s Beckman Institute Biological and Cryogenic Transmission Electron Microscopy (Cryo-EM) Resource Center. Flippases such as MurJ move molecules by alternately exposing them to each side of the membrane without forming a permanent opening. When MurJ binds its cargo inside the cell, it changes shape to release the molecule on the outside.

Li found that both SglM and SglPP7 attach to a groove in MurJ, preventing the structural shift required for transport.

“It is clear that both of these Sgls bind to MurJ in an outward-facing conformation, locking it into this position,” Li says. Researchers are encouraged by this because the outward-facing form of MurJ is exposed to the surrounding environment, which could make it more accessible to future drugs than a conformation that faces inward.

Convergent Evolution Highlights a Promising Drug Target

Clemons says the result was surprising for another reason. “These peptides, which have no evolutionary links to each other, have both figured out how to target MurJ in a very similar way. These are two examples of convergent evolution, in which different evolutionary paths arrive at the same solution. We were surprised!”

Because viruses evolve rapidly, the team believes many more phages likely carry similar Sgls. Phages are relatively easy to isolate, and studying their genomes could reveal additional biological insights and new antibiotic targets.

In the Nature study, the researchers analyzed another phage genome with the help of a collaborator. They identified a new Sgl called SglCJ3 (from a genome sequence that is predicted to be a phage and is called Changjiang3) and examined it using cryo electron microscopy. Li determined the structure of SglCJ3 bound to MurJ and found that it also locks the protein in the same outward-facing conformation.

“This is a third genome that evolved a distinct peptide to inhibit the same target in a similar way,” Clemons says. “It is the first strong evidence that evolution identifies MurJ as a great target for killing bacteria, which means we should follow evolution’s lead and develop therapeutics that target MurJ. This demonstrates the power of basic biology to help us solve problems in medicine. Our path is set on leveraging Sgl discovery, and we hope to continue to be supported to turn these concepts into realities.”

Authors and Funding

The paper is titled “Convergent MurJ flippase inhibition by phage lysis proteins.” In addition to Clemons and Li, the authors include Caltech graduate student Grace F. Baron and Francesca S. Antillon, Karthik Chamakura, and Ry Young of Texas A&M University. The research was supported by the Chan Zuckerberg Initiative, the National Institutes of Health, the G. Harold and Leila Y. Mathers Foundation, and the Center for Phage Technology at Texas A&M, jointly sponsored by Texas A&M AgriLife.