Sulfonamides are a cornerstone of modern medicinal chemistry, forming part of many antibacterial, anticancer and antiviral medicines. Yet despite their widespread use, producing sulfonamides synthetically can be difficult, often requiring harsh reagents and generating environmentally damaging by‑products. Natural examples of sulfonamide‑containing molecules are extremely rare, and until now very little was known about how biological systems make them.

International collaboration cracks the code

The international research team – including computational chemist Dr and PhD student from the MIB – has uncovered how the enzyme SbzM enables bacteria to form sulfonamides as part of the biosynthesis of the natural product altemicidin. Their work shows that SbzM uses nickel, rather than the more common iron cofactor found in related enzymes, to convert the amino acid L‑cysteine into a reactive sulfonamide intermediate.

Using a combination of structural biology, biochemical assays and advanced quantum‑mechanical computational modelling, the researchers showed that SbzM performs chemistry never before observed in nature. The study reveals:

• SbzM is strictly nickel‑dependent, requiring Ni²⁺ to function and cycling between Ni²⁺ and Ni³⁺ during the reaction.
• Two separate oxygen molecules are incorporated into the final sulfonamide product, a striking contrast to iron‑based cysteine dioxygenases, which use a single oxygen molecule.
• A previously unknown reaction pathway is at work: the enzyme first triggers an oxidative decarboxylation step to form a mercaptoimine intermediate, followed by sequential oxygenation and rearrangement steps that ultimately build the sulfonamide group.
• The enzyme family is far more widespread in bacteria than previously recognised, suggesting nature may harbour many more yet‑undiscovered sulfonamide biosynthetic pathways.

Understanding how nature constructs sulfonamide motifs opens a realistic route to engineering enzymes capable of producing drug-like building blocks more sustainably. The 91ֱ�� team’s computational modelling was essential in mapping the step‑by‑step reaction mechanism and identifying why nickel, uniquely, drives this transformation, and by revealing the fundamental “instruction manual” behind sulfonamide formation, the study lays essential groundwork for creating scalable, low waste biocatalytic processes for pharmaceutical manufacturing.

The next steps will focus on expanding the range of molecules SbzM can process, enhancing its robustness, and demonstrating industrially relevant biocatalysis.

Meet the researchers

Sam de Visser Reader in Computational Chemistry at the 91ֱ�� Institute of Biotechnology, investigates inorganic mechanisms in first‑row transition‑metal enzymes using quantum chemistry and molecular dynamics, focusing on heme and nonheme iron enzyme reactivity.

• Email Dr de Visser >>

Henrik Wong is a University of Manchester PhD student using molecular dynamics and quantum chemistry to study metal‑dependent enzymes and guide their redesign for sustainable biocatalysis, reaction discovery and improved biosynthetic applications.

• Email Mr Wong >>

The five-year multi-centre research project – supported by £10mn funding from Wellcome – involves researchers from the Universities of Cambridge, Kent, 91ֱ��, Oxford, and Imperial College London. SynHG is led by Professor Jason Chin of the MRC Laboratory of Molecular Biology; he was also recently announced as the founding Director of the Generative Biology Institute at the Ellison Institute of Technology, Oxford, and a Professor at the University of Oxford.

A dedicated social science programme, led by Professor Joy Zhang of the Centre for Global Science and Epistemic Justice at the University of Kent, runs throughout the project alongside the scientific development. The programme will work with civil society partners around the world to actively explore, assess and respond to the socio-ethical implications of tools and technologies developed by SynHG.

The benefits of human genome synthesis to research and beyond 
Since the completion of the Human Genome Project at the start of the century, researchers have sought the ability to write our genome from scratch. Unlike genome editing, genome synthesis allows for changes at a greater scale and density, with more accuracy and efficiency, and will lead to the determination of causal relationships between the organisation of the human genome and how our body functions. Synthetic genomes have the potential to open up brand new areas of research in creating targeted cell-based therapies, virus-resistant tissue transplantation and extensions may even enable the engineering of plant species with new properties, including the ability to withstand harsh climate. 

To date, scientists have successfully developed synthetic genomes for microbes such as E. coli. The field of synthetic genomics has accelerated in recent times, and advances in machine learning, data science and AI showing promise, with synthesised DNA becoming more widely available. However, today’s technology is not able to produce large, more complex sections of genetic material, such as found in crops, animals and humans. 

The research team are focusing on developing the tools and technology to synthesise large genomes exemplified by the human genome. Focusing on the human genome, as opposed to other model organisms such as mice, will allow researchers to more quickly make transformative discoveries in human biology and health.

 Professor Jason Chin, Founding Director of the Generative Biology Institute at EIT, Oxford, said: “The ability to synthesize large genomes, including genomes for human cells, may transform our understanding of genome biology and profoundly alter the horizons of biotechnology and medicine. With SynHG we are building the tools to make large genome synthesis a reality, and at the same time we are pro-actively engaging in the social, ethical, economic and policy questions that may arise as the tools and technologies advance.  We hope that Wellcome’s support for this combination of approaches will help facilitate substantive societal benefit.”

A bold, ambitious project facing complex scientific challenges 
SynHG focuses on developing the foundational tools and methods required to equip more researchers in the future. This research journey will potentially catalyse new technologies in the field of engineering biology, generating exciting discoveries about how cells use their genomes even before achieving complete genome synthesis. 

The team of researchers hope to provide proof of concept for large genome synthesis by creating a fully synthetic human chromosome, which makes up approximately 2% of our total DNA. Initially, the team hope to establish methods where small changes are made to the sequence of a chromosome with minimal onward effect on the proteins that it produces. 

Setting the foundation – testing the concept, iterating the methods, and embedding ethical considerations – could alone take many years. Even as engineering biology technologies improve, reliably building a complete synthetic human genome and meaningfully applying it to human health will likely take decades.

Michael Dunn, Director of Discovery Research at Wellcome, said: “Our DNA determines who we are and how our bodies work and with recent technological advances, the SynHG project is at the forefront of one of the most exciting areas of scientific research. Through creating the necessary tools and methods to synthesise a human genome we will answer questions about our health and disease that we cannot even anticipate yet, in turn transforming our understanding of life and wellbeing.” 

Professor Patrick Yizhi Cai, Chair of Synthetic Genomics at the University of Manchester said: "We are leveraging cutting-edge generative AI and advanced robotic assembly technologies to revolutionize synthetic mammalian chromosome engineering. Our innovative approach aims to develop transformative solutions for the pressing societal challenges of our time, creating a more sustainable and healthier future for all."

Embedding global socio-ethical discussions in scientific advancements 
To effectively translate scientific ambition into meaningful and potentially profound societal benefits, it is essential that there is proactive and sustained engagement with the evolving socio-ethical priorities and concerns of diverse communities. 

Wellcome is also funding Care-full Synthesis, a dedicated social research initiative conducting empirical studies with diverse publics worldwide. Led by Professor Joy Y. Zhang and hosted by the Centre for Global Science and Epistemic Justice (GSEJ) at the University of Kent, the project builds on GSEJ’s global network of academic, civil society, industry and policy partners to promote a new approach of science–society dialogue that is Open, Deliberative, Enabling, Sensible & Sensitive, and Innovative (‘ODESSI’). 

Professor Joy Zhang, Founding Director of the GSEJ at the University of Kent said: “With Care-full Synthesis, through empirical studies across Europe, Asia-Pacific, Africa, and the Americas, we aim to establish a new paradigm for accountable scientific and innovative practices in the global age—one that explores the full potential of synthesising technical possibilities and diverse socio-ethical perspectives with care.” 

Over the next five years, the team will undertake a transdisciplinary and transcultural investigation into the socio-ethical, economic, and policy implications of synthesising human genomes. The project places particular emphasis on fostering inclusivity within and across nation-states, while engaging emerging public–private partnerships and new interest groups. 

Through the generation of rich empirical data, the team will develop a toolkit to enable effective integration of careful thinking into the management, communication, and delivery of human genome synthesis. This work aims to substantially expand the practice of accountable science and innovation, reflecting the complex realities of a hyperconnected yet ideologically fragmented world. Care-full Synthesis will achieve this by advancing a fresh approach to engaging with global communities, ensuring that fast-moving science is accompanied by robust social and legal deliberation, and identifying innovative strategies to co-ordinate regional and global governance accounting for diverse social priorities and scientific pathways.

As the UK strives to reach Net Zero emissions by 2050, secure and permanent geological storage of CO₂ is essential to avoid the worst-case consequences of climate change.

Storage in deep geological formations such as depleted oil and gas reservoirs and saline aquifers offers a promising solution. However, these underground environments host diverse microbial ecosystems, and their response to CO₂ injection remains poorly understood.

This knowledge gap poses a potential risk to long-term CO₂ storage integrity. While some microbial responses may be beneficial and enhance mineralogical or biological CO₂ sequestration, others could be unfavourable, leading to methane production, corrosion of infrastructure, or loss of injectivity.

The new flagship project with The University of Manchester and Equinor - global leaders in geological CO₂ storage - will investigate how subsurface microbial communities respond to CO₂ injection and storage, highlighting both the potential risks and opportunities posed by these microbes.

Principal Investigator, Prof Sophie Nixon, BBSRC David Phillips and Dame Kathleen Ollerenshaw Fellow at The University of Manchester, said: "Over the past 20 years, scientists have tested storing CO₂ underground in real-world conditions, but we still know little about how this affects native and introduced microbes living deep below the surface.

"Previous studies have shown that injecting CO₂ underground actively changes microbial communities. In some cases, microbes initially decline but later recover, potentially influencing the fate of injected CO₂ in geological storage scenarios. However, these studies predate the advent of large-scale metagenomic sequencing approaches. A deep understanding of who is there, what they can do and how they respond to CO₂ storage is crucial for ensuring the long-term success of carbon capture and storage."

The two-year project will collect samples from saline aquifer and oil producing sites to study how microbes living deep underground respond to high concentrations of CO₂ by combining geochemistry, gas isotope analysis, metagenomic and bioinformatic approaches.

Project Co-Investigator, Dr Rebecca Tyne, a Dame Kathleen Ollerenshaw Fellow at The University of Manchester, said: “To date, Carbon Capture and Storage research has focused on the physiochemical behaviour of CO₂, yet there has been little consideration of the subsurface microbial impact on CO₂ storage. However, the impact of microbial processes can be significant. For instance, my research has shown that methanogenesis may modify the fluid composition and the fluid dynamics within the storage reservoir.”

Currently, the North Sea Transition Authority requires all carbon capture and storage sites to have a comprehensive ‘Measurement, Monitoring and Verification’ strategy, but microbial monitoring is not yet included in these frameworks. The project’s findings will be shared with industry stakeholders and published in leading scientific journals, helping to close this critical gap and shape future operational activities.

Project Lead, Leanne Walker, Research Associate in Subsurface Microbiology at The University of Manchester, said: "This project will help us understand the underground microbial communities affected by CO₂ storage—how they respond, the potential risks and benefits, and the indicators that reveal these changes.

"Our findings will provide vital insights for assessing microbiological risks at both planned and active CCS sites, ensuring safer and more effective long-term CO₂ storage”.

Biotechnology is enabling us to find new and more sustainable ways to produce chemicals, materials, and everyday products, by understanding and harnessing nature’s own processes and applying them at industrial scales. Supported by the 91ֱ�� Institute of Biotechnology, our 400+ experts are innovating solutions in environmental sustainability, health and sustainable manufacturing. Find out more about our biotechnology research.  

Enzymes are proteins that catalyse chemical reactions, turning one substance into another. In labs, scientists engineer these enzymes to perform specific tasks like the sustainable creation of medicines, and materials. These biocatalysts have many environmental benefits as they often produce higher product quality, lower manufacturing cost, and less waste and reduced energy consumption. But to find ‘the one’, scientists must test hundreds of variants for their effectiveness, which is a slow, expensive, and resource-intensive process.

Research conducted by The University of Manchester in collaboration with AstraZeneca is changing this. The team developed a method for a technique that can test enzyme activity up to 1,000 times faster than traditional methods. The new method, developed over the last eight years and detailed today in the journal  is called DiBT-MS (Direct Analysis of Biotransformations with Mass Spectrometry).

It builds on an existing technology called DESI-MS (Desorption Electrospray Ionization Mass Spectrometry), a powerful tool that allows scientists to analyse complex biological samples without the need for extensive sample preparation. 

By making small adaptations to the technology, the scientists designed a protocol to directly analyse enzyme-triggered chemical reactions, known as biotransformations, in just minutes. The new method can process 96 samples in just two hours—tasks that would previously take days using older techniques.

It has also been optimised to allow the researchers to reuse sample slides multiple times improving testing efficiency and decreasing the use of solvents and plasticware.

The team has already successfully applied this technique to a range of enzyme-driven reactions, including those enzymes particularly valuable in the development of therapeutics.

Looking ahead, The University of Manchester will continue to explore ways to boost partnerships between laboratories and tackle other challenges that often hinder collaboration, such as geographical barriers and limited funding.

This research was partly funded by a UKRI Prosperity Partnership grant in collaboration with AstraZeneca.

Journal: Nature Protocols

Full title: Direct analysis of biotransformations with mass spectrometry—DiBT-MS

DOI: 10.1038/s41596-025-01161-9

Link:

A group of leading international scientists is calling for a global conversation about the potential creation of "mirror bacteria"—a hypothetical form of life built with biological molecules that are the opposite of those found in nature.

In a new report published today in the journal , the researchers, including Professor Patrick Cai, a world leader in synthetic genomics and biosecurity, from The University of Manchester, explain that these mirrored organisms would differ fundamentally from all known life and could pose risks to ecosystems and human health if not carefully managed.

Driven by scientific curiosity, some researchers around the world are beginning to explore the possibility of creating mirror bacteria, and although the capability to engineer such life forms is likely decades away and would require major technological breakthroughs, the researchers are calling for a broad discussion among the global research community, policymakers, research funders, industry, civil society, and the public now to ensure a safe path forward.

Professor Cai said: “While mirror bacteria are still a theoretical concept and something that we likely won’t see for a few decades, we have an opportunity here to consider and pre-empt risks before they arise.

“These bacteria could potentially evade immune defences, resist natural predators, and disrupt ecosystems. By raising awareness now, we hope to guide research in a way that prioritises safety for people, animals, and the environment."

The analysis is conducted by 38 scientists from nine countries including leading experts in immunology, plant pathology, ecology, evolutionary biology, biosecurity, and planetary sciences. The publication in is accompanied by a detailed 300-page .

The analysis concluded that mirror bacteria could broadly evade many immune defences of humans, animals, and potentially plants.

It also suggests that mirror bacteria could evade natural predators like viruses and microbes, which typically control bacterial populations. If they were to spread, these bacteria could move between different ecosystems and put humans, animals, and plants at continuous risk of infection.

The scientists emphasise that while speculative, these possibilities merit careful consideration to ensure scientific progress aligns with public safety.

Professor Cai added: “At this stage, it’s also important to clarify that some related technologies, such as mirror-image DNA and proteins, hold immense potential for advancing science and medicine. Similarly, synthetic cell research, which does not directly lead to mirror bacteria, is critical to advancing basic science. We do not recommend restricting any of these areas of research. I hope this is the starter of many discussions engaging broader communities and stakeholders soon. We look forward to hosting a forum here in 91ֱ�� in autumn 2025.”

Going forward, the researchers plan to host a series of events to scrutinise their findings and encourage open discussion about the report. For now, they recommend halting any efforts toward the creation of mirror bacteria and urge funding bodies not to support such work. They also propose examining the governance of enabling technologies to ensure they are managed responsibly.

Biocatalysis is a process that uses enzymes as natural catalysts to carry out chemical reactions. Scientists at The University of Manchester and AstraZeneca have developed a new biocatalytic pathway that uses enzymes to produce nucleoside analogues, which are vital components in many pharmaceuticals used to treat conditions like cancer and viral infections.

Typically, producing these analogues is complicated, time consuming and generates significant waste. However, in a new breakthrough, published in the journal , the researchers have demonstrated how a "biocatalytic cascade" — a sequence of enzyme-driven reactions — can simplify the process, potentially cutting down production time and reducing environmental impact.

The researchers engineered an enzyme called deoxyribose-5-phosphate aldolase, enhancing its range of functions to efficiently produce different sugar-based compounds, which serve as building blocks for nucleoside-based medicines, such as oligonucleotide therapeutics. These building blocks were combined using additional enzymes to develop a condensed protocol for the synthesis of nucleoside analogues which simplifies the traditional multi-step process to just two or three stages, significantly improving efficiency.

With further refinement, this method could help streamline the production of a wide range of medicines, while significantly reducing their environmental footprint. The team are now continuing this work with the MRC funded , which looks to develop sustainable biocatalytic routes towards functionalised nucleosides, nucleotides and oligonucleotides.

These findings have the potential to accelerate the discovery of novel, more efficient cryoprotectants - and may also allow for the repurposing of molecules already known to slow or stop ice growth.

Professor Matthew Gibson, from 91ֱ�� Institute of Biotechnology at The University of Manchester, added: “My team has spent more than a decade studying how ice-binding proteins, found in polar fish, can interact with ice crystals, and we’ve been developing new molecules and materials that mimic their activity. This has been a slow process, but collaborating with Professor Sosso has revolutionized our approach. The results of the computer model were astonishing, identifying active molecules I never would have chosen, even with my years of expertise. This truly demonstrates the power of machine learning.”

The full paper can be read .

Peptides are comprised of small chains of amino acids, which are also the building blocks of proteins. Peptides play a crucial role in our bodies and are used in many medicines to fight diseases such as cancer, diabetes, and infections. They are also used as vaccines, nanomaterials and in many other applications. However, making peptides in the lab is currently a complicated process involving chemical synthesis, which produces a lot of harmful waste that is damaging to the environment.

In a new breakthrough, published in the journal , 91ֱ�� scientists have discovered a new family of ligase enzymes – a type of molecular glue that can help assemble short peptide sequences more simply and robustly, yielding significantly higher quantities of peptides compared to conventional methods.

The breakthrough could revolutionise the production of treatments for cancer and other serious illnesses, offering a more effective and environmentally friendly method of production.

For many years, scientists have been working on new ways to produce peptides. Most existing techniques rely on complex and heavily protected amino acid precursors, toxic chemical reagents, and harmful volatile organic solvents, generating large amounts of hazardous waste. The current methods also incur high costs, and are difficult to scale up, resulting in limited and expensive supplies of important peptide medicines.

The team in 91ֱ�� searched for new ligase enzymes involved in the biological processes that assemble natural peptides in simple bacteria. They successfully isolated and characterised these ligases and tested them in reactions with a wide range of amino acid precursors. By analysing the sequences of the bacterial ligase enzymes, the team identified many other clusters of ligases likely involved in other peptide pathways.

The study provides a blueprint for how peptides, including important medicines, can be made in the future.

, who also worked on the project said, “The ligases we discovered provide a very clean and efficient way to produce peptides. By searching through available genome sequence data, we have found many types of related ligase enzymes. We are confident that using these ligases we will be able to assemble longer peptides for a range of other therapeutic applications.”

Following the discovery, the team will now optimise the new ligase enzymes, to improve their output for larger scale peptide synthesis. They have also established collaborations with a number of the top pharmaceutical companies to help with rolling out the new ligase enzyme technologies for manufacturing future peptide therapeutics.