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By Daniella Gray
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Scientists have cracked how bacteria build cancer-fighting compounds, a breakthrough that could speed up new treatments.
The study, published in Nature Communications, reveals how different enzyme systems “plug together” to build a family of drugs known as HDAC inhibitors—compounds that interfere with cancer cell growth.
"This discovery has the potential to significantly accelerate the creation of libraries of drug candidates and, importantly, should enable those with the most promise to be manufactured at scale for a reasonable cost," Dr. Munro Passmore, from the University of Warwick, told Newsweek.
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However, he cautioned that any new therapies would still take time to reach patients.
"Notwithstanding this, the most promising candidates will still need to follow the usual process of preclinical testing, further optimization and clinical evaluation that new drugs invariably undergo prior to being approved for use in patients," Passmore said. "This can take up to decade and often costs more than $1 billion."
This family of drugs includes romidepsin, an established therapy for certain blood cancers.
Scientists have long known that bacteria naturally produce similar compounds with subtle variations, but how these variations arise has remained unclear.
At the heart of the discovery is a process called combinatorial biosynthesis, in which bacteria generate multiple related molecules by mixing and matching biochemical components.
Many medically important molecules are built by large enzyme complexes that function like assembly lines. In bacteria, two major systems—polyketide synthases (PKSs) and nonribosomal peptide synthetases (NRPSs)—combine chemical building blocks to form complex compounds, including antibiotics and anticancer drugs.
The study focused on a hybrid of these systems responsible for producing depsipeptide HDAC inhibitors, a class of molecules that share a common “core” structure but differ in an attached peptide segment.
These structural differences influence how the drugs interact with their targets.
Researchers discovered that the enzymes responsible for building the core and those adding the variable peptide segment can physically connect through specific “docking” interactions.
This allows different parts of the molecular machinery to work together, effectively creating new combinations of drug-like compounds.
A key breakthrough was identifying how these enzyme components recognize and bind to each other. The team showed that a structural feature known as a β-hairpin docking (βHD) domain plays a central role, allowing one enzyme system to engage with another and pass intermediate molecules along the assembly line.
Experiments confirmed that disrupting this interaction prevents production of the target compound, underlining its importance in the process.
The researchers also demonstrated that enzyme systems from different biosynthetic pathways can interact with one another, suggesting a level of flexibility that could be exploited to generate entirely new molecules.
Professor Greg Challis of University of Warwick said this flexibility could be particularly valuable for tackling cancers that are difficult to treat with existing therapies.
"Initial data suggest the class of drugs produced by the 'mix-and-match' mechanism has promising activity against several types of cancer that don’t respond well to existing treatments," he told Newsweek.
"Harnessing the 'mix and match' mechanism in a laboratory setting should enable new members of this drug class with enhanced clinical potential to be discovered and their production should be readily scalable, facilitating pre-clinical and clinical investigation," he said.
Contact Newsweek editors on this story: Kara Dolman and Emma Lee-Sang.
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