A team of\u00a0researchers\u00a0at the\u00a0University of\u00a0Warwick\u00a0and Monash University\u00a0has\u00a0solved a puzzle that’s stumped drug developers for decades: how bacteria naturally\u00a0create\u00a0multiple versions of powerful cancer therapies. The breakthrough could accelerate development of new treatments for hard-to-treat cancers.\u00a0<\/p>\n
Harnessing bacterial enzymes to create drug variants,\u00a0a strategy known as combinatorial biosynthesis,\u00a0has\u00a0long\u00a0been\u00a0a goal for\u00a0scientists.\u00a0But without understanding how these enzymes interact, progress has stalled.\u00a0<\/p>\n
Published\u00a0in\u00a0Nature Communications,\u00a0a team of\u00a0researchers have finally\u00a0revealed\u00a0how bacterial enzymes communicate and\u00a0work together\u00a0to assemble a family of related anti-cancer compounds. This family\u00a0includes\u00a0Romidepsin (Istodax), a clinically approved blood cancer treatment. By understanding this “mix and match” process,\u00a0and replicating the principle in the lab, the researchers have\u00a0established\u00a0an\u00a0approach to\u00a0designing new therapies.\u00a0<\/p>\n
“For decades, we’ve known that bacteria can naturally\u00a0produce\u00a0multiple versions of powerful anti-cancer drugs, yet we had no\u00a0idea how\u00a0they achieved this,”\u00a0said first author\u00a0Dr. Munro Passmore, Research Fellow, Department of Chemistry, University of Warwick.\u00a0“This work finally cracks that code.\u00a0We’ve\u00a0identified\u00a0how the different enzymes communicate and cooperate to\u00a0produce\u00a0these\u00a0drug\u00a0variants, something that has eluded researchers because the system is so elegantly economical.\u00a0It’s\u00a0the breakthrough we needed to\u00a0actually engineer\u00a0these drugs ourselves.”\u00a0<\/p>\n
The team’s analysis reveals that small molecular regions, termed ‘docking domains,’ act as connectors between the core drug assembly machinery and the variable component-building enzymes. Crucially, these docking domains use a conserved connection point that is compatible with multiple different enzyme partners,\u00a0a feature that explains how bacteria generate structural diversity while keeping their drugs precise and effective.\u00a0<\/p>\n
The work also traces how\u00a0these\u00a0drug-producing systems evolve naturally. The researchers found that the newly discovered compound\u00a0likely evolved\u00a0from a related drug-producing system through gene duplications and\u00a0recombinations.\u00a0<\/p>\n
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This\u00a0research\u00a0gives us a blueprint to do what nature does, but better and faster. By reverse-engineering nature’s evolutionary\u00a0logic, we can now design synthetic pathways that generate new anti-cancer drug candidates with properties\u00a0optimized\u00a0for clinical use, such as\u00a0superior potency, improved selectivity, fewer side effects. Our immediate goal is to build an expanded library of candidates for\u00a0various\u00a0cancers where\u00a0new\u00a0treatments\u00a0are urgently needed.\u00a0This discovery is\u00a0moving\u00a0us\u00a0from understanding how\u00a0the systems\u00a0work to building\u00a0new ones.”\u00a0<\/p>\n
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Prof. Greg Challis, Monash Warwick Alliance Professor of Sustainable Chemistry, University of Warwick and Monash University<\/p>\n
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