Scientists finally crack nature's secret for building better cancer drugs

Scientists have uncovered how bacteria naturally manufacture multiple versions of powerful cancer drugs, solving a mystery that has puzzled researchers for decades. The discovery could help speed the development of new treatments for cancers that are still difficult to treat.

For years, scientists have hoped to harness bacterial enzymes to create new drug variants through a process known as combinatorial biosynthesis. However, progress has been limited because researchers did not fully understand how the enzymes coordinate their work.

Published in Nature Communications, the new study reveals how bacterial enzymes communicate with one another to assemble a family of closely related anti-cancer compounds. That family includes Romidepsin (Istodax), an FDA-approved treatment for certain blood cancers. By uncovering this natural "mix and match" system and reproducing its underlying principles in the laboratory, the researchers have established a new strategy for designing future cancer therapies.

"For decades, we've known that bacteria can naturally produce multiple versions of powerful anti-cancer drugs, yet we had no idea how they achieved this," said first author Dr. Munro Passmore, Research Fellow, Department of Chemistry, University of Warwick. "This work finally cracks that code. We've identified how the different enzymes communicate and cooperate to produce these drug variants, something that has eluded researchers because the system is so elegantly economical. It's the breakthrough we needed to actually engineer these drugs ourselves."

Tiny Molecular Connectors Reveal Nature's Drug-Making Strategy

The researchers discovered that small molecular regions known as 'docking domains' serve as connectors between the core drug-building machinery and the enzymes responsible for adding different components. These docking domains share a conserved connection point that allows them to interact with multiple enzyme partners.

This flexible design explains how bacteria can create a variety of related drug molecules while still maintaining the precision needed for the compounds to remain effective.

The study also sheds light on how these natural drug-producing systems evolved. According to the researchers, the newly identified compound most likely developed from a related drug-producing pathway through gene duplication and recombination over time.

Prof. Greg Challis, Monash Warwick Alliance Professor of Sustainable Chemistry, University of Warwick and Monash University concludes: "This research gives us a blueprint to do what nature does, but better and faster. By reverse-engineering nature's evolutionary logic, we can now design synthetic pathways that generate new anti-cancer drug candidates with properties optimized for clinical use, such as superior potency, improved selectivity, fewer side effects. Our immediate goal is to build an expanded library of candidates for various cancers where new treatments are urgently needed. This discovery is moving us from understanding how the systems work to building new ones."

How the Discovery Could Improve Cancer Drug Development

The work focuses on a class of anti-cancer medicines known as HDAC inhibitors. These drugs block histone deacetylases, enzymes that help regulate which genes are switched on or off inside cells. Romidepsin (Istodax) is an FDA-approved HDAC inhibitor used to treat T-cell lymphomas.

A chemically related compound called FR-901375 has been known for decades, but scientists had never identified the biological pathway bacteria use to produce it. This study finally fills in that missing piece.

Like other HDAC inhibitors in its family, FR-901375 belongs to a group of complex cyclic molecules called depsipeptides. These compounds are assembled from amino acid building blocks along with a conserved hydroxy acid pharmacophore, all connected through a combination of peptide and ester bonds.

Inside bacteria, these molecules are built by massive protein complexes called PKS-NRPS hybrids, which combine the activities of polyketide synthase (PKS) and nonribosomal peptide synthetase (NRPS). The new research shows that the key to this assembly process is the docking domains, which act like molecular connectors that allow one part of the production line to recognize and pass its product to the next. This mechanism is what enables combinatorial biosynthesis and allows bacteria to naturally generate multiple drug variants.

How the Researchers Solved the Mystery

To uncover how this system works, the team combined structural biology, biochemistry, genetics, and computational modeling.

Their work included:

• Bioinformatic searches of public databases that identified the FR-901375 biosynthetic gene cluster in Pseudomonas chlororaphis subsp. piscium, with the findings confirmed by mass spectrometry analysis of extracted metabolites.
• In vitro reconstitution experiments using purified protein domains that demonstrated productive enzyme-enzyme interactions, verified with intact protein mass spectrometry.
• AlphaFold computational modeling to predict protein complex structures, followed by carbene footprinting mass spectrometry to experimentally map the interaction sites.
• Site-directed mutagenesis experiments that confirmed the importance of the predicted binding residues.
• Gene deletion studies in bacterial strains showing that the docking domains are essential for the system to function in vivo.
• Comparative analysis of biosynthetic gene clusters from multiple HDAC inhibitor-producing bacteria, revealing evolutionarily conserved features shared across these natural drug-making systems.

Journal Reference:

1. Munro Passmore, Xinyun Jian, Xinyi Zhao, Emmanuel L. C. de los Santos, Douglas M. Roberts, Józef R. Lewandowski, Matthew Jenner, Lona M. Alkhalaf, Gregory L. Challis. Molecular basis for depsipeptide HDAC inhibitor combinatorial biosynthesis. Nature Communications, 2026; 17 (1) DOI: 10.1038/s41467-026-74383-4

Courtesy:

University of Warwick. "Scientists finally crack nature's secret for building better cancer drugs." ScienceDaily. ScienceDaily, 8 July 2026. <www.sciencedaily.com/releases/2026/07/260701205001.htm>.

 

 

 

Alzheimer's tau protein has a surprising secret role in memory

New research has revealed that tau, a protein best known for its connection to Alzheimer's disease, is also essential for creating long lasting memories. The discovery provides new insight into how healthy memory works and could help guide future efforts to develop treatments for dementia.

The study, led by Flinders University in partnership with researchers from the University of New South Wales and Macquarie University, was published in Nature Communications. It found that tau helps organize and stabilize memories so they can be retained over time.

The researchers studied "remote memory" in mice, which refers to memories recalled days or weeks after an experience. They discovered that tau is not necessary for learning something new or remembering it shortly afterward. Instead, it plays a crucial role in making those memories durable over the long term.

Because the research was conducted in mice, the findings cannot be directly applied to human memory or Alzheimer's disease. Even so, the results offer valuable clues that could shape future dementia research and treatment strategies.

Tau's Role in Long Lasting Memory

Senior author Associate Professor Arne Ittner, a neuroscientist from Flinders' College of Medicine and Public Health, says the findings help explain why people with dementia may still be able to learn new information initially, yet struggle to retain it.

"Why some memories last while others fade has long puzzled scientists and our study shows that tau plays a key role in how the brain forms long-lasting memories. Without it, memories can still form in the moment, but they are weaker," says Associate Professor Ittner.

The team focused on specialized brain cells called "engram cells," which create the physical record of a memory. When a new experience occurs, only a small number of these cells are selected to store it.

According to the study, tau is active during this critical stage of memory formation, helping determine exactly which engram cells are recruited to preserve the experience.

One of the study's lead authors, Renée Kosonen, says tau acts like an organizer that helps the brain build accurate and lasting memories.

"Our findings show that tau helps determine which cells are selected to store a memory, shaping how an experience forms a lasting memory trace," says Ms Kosonen, a researcher at Flinders' Neuroscience and Dementia Research.

How Tau Organizes Memory

The researchers also found that tau reduces unnecessary or "noise" activity in the brain during memory formation. By limiting this background activity, tau allows only a specific group of cells to become part of a memory, producing clearer and more stable memory traces.

The team identified an important molecular process behind this effect. As learning takes place, tau undergoes a subtle chemical change called phosphorylation, which helps coordinate the activity of engram cells.

Although abnormal tau phosphorylation is a well known feature of Alzheimer's disease, the study shows that controlled, low level phosphorylation is a normal and essential part of healthy brain function.

New Clues About Alzheimer's Disease

The researchers made another surprising discovery. Even in the absence of tau, memory traces still existed and could be recovered by directly stimulating engram cells. This suggests that tau is not required to store memories themselves. Instead, it appears to be needed to connect natural cues, such as sights and sounds, with the ability to recall those memories.

The findings also provide new insight into how Alzheimer's related tau may interfere with memory. When disease associated forms of tau were present in engram cells during learning, they disrupted the creation of new memories. When those abnormal forms appeared after memories had already formed, they interfered with the brain's ability to retrieve them.

These effects were associated with abnormal patterns of brain activity, suggesting that memory problems in dementia may result not only from memories being lost, but also from disruptions in how memories are organized and accessed.

"Knowing how tau supports the formation and recall of memory could help us better understand what goes wrong in memory loss," says Associate Professor Ittner.

"Future research will hopefully be able to confirm concepts developed in our study in human memory and show their implication in dementia."

The researchers conclude that tau should be viewed not only as a protein involved in Alzheimer's disease, but also as a fundamental regulator of how the brain organizes, stores, and retrieves lasting memories. That new perspective could deepen scientists' understanding of both healthy memory and the biological changes that contribute to Alzheimer's disease.

Journal Reference:

1. Renée Kosonen, Kristie Stefanoska, Yijun Lin, Samantha Edwards, Emmanuel Prikas, Josefine Bertz, Anne Poljak, Lars M. Ittner, Arne Ittner. Tau T205 phosphorylation modulates engram cell recruitment and remote memory in mice. Nature Communications, 2026; DOI: 10.1038/s41467-026-73207-9

Courtesy:

Flinders University. "Alzheimer's tau protein has a surprising secret role in memory." ScienceDaily. ScienceDaily, 12 July 2026. <www.sciencedaily.com/releases/2026/07/260710003535.htm>.