Bacteria assemble complex molecules called polyketides, which are the basis for antibiotics like gladiolin and anticancer agents like gladiostatin, but the enzymes that control their final structure remain poorly understood. This research focuses on enoylreductase (ER) enzymes that modify polyketides during their assembly inside bacterial cells. The problem is that these natural molecules often need structural tweaks—changing their degree of unsaturation or chain length—to work better as drugs or agricultural chemicals. Synthetic chemistry struggles to make those modifications because the molecules are too complex, and the process relies on petrochemicals, consumes energy, and generates toxic waste. The team aims to reveal how trans-acting ERs are recruited to specific sites on polyketide synthases and how they suppress unwanted repetition in the assembly process. If successful, this fundamental knowledge could enable bioengineering approaches to produce optimised polyketide derivatives through fermentation—cheaper, greener, and using sustainable plant feedstocks. This is primarily curiosity-driven bioscience, but similar mechanistic work on bacterial assembly lines has previously unlocked routes to improved antibiotics and agrochemicals.
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Bacteria are remarkable chemists capable of assembling complex molecules that enter cells and bind biomolecular targets with high affinity and selectivity. Consequently, bacterial natural products have wide-ranging applications in medicine (as antibiotics, anticancer agents, and immunomodulators) and agriculture (as insecticides, fungicides, and herbicides). How the "blind watchmaker" of evolution creates structurally diverse molecular architectures is a key question in contemporary biosynthesis research. In this proposal, we seek to illuminate how enoylreductase (ER) enzymes contribute to structural diversification of an important class of bacterial natural products called polyketides by understanding how trans-acting ERs are recruited to and suppress iteration in specific modules of trans-acyltransferase (trans-AT) polyketide synthases (PKSs). The specific objectives of our proposal are: Establish the structural basis for productive interaction between trans-acting ERs and specific acyl carrier protein domains in trans-AT PKSs. Elucidate the substrate tolerance and catalytic mechanism of trans-acting ERs involved in the assembly of the antibiotic gladiolin and the anticancer agent gladiostatin. Investigate the generality and molecular mechanism for suppression of trans-AT PKS module iteration by trans-acting ERs. The knowledge gained from this interdisciplinary research will enable the development of bioengineering approaches to alter the degree of unsaturation and chain length of polyketide natural products, which often require structural modification to optimise them for therapeutic or agricultural application. Structural modification of polyketides using synthetic chemistry is challenging due to their complexity. Moreover, such methods rely on non-renewable petrochemical feedstocks, are energy intensive, create environmentally damaging byproducts, and are expensive. In contrast, structural modification of polyketides via bioengineering enables optimised derivatives to be produced via fermentation, which is cheaper, more energy efficient, has lower environmental impact, and utilises sustainable plant-derived feedstocks. This research is directly relevant to the Engineering Biology theme of BBSRC's Transformative Technologies priority of the Advancing the Frontiers of Bioscience Discovery high level objective. It also aligns with the Sustainable Agricultural Systems focus area of the Bioscience for Sustainable Agriculture and Food priority, the Production of More Sustainable Products focus area of the Bioscience for Advanced Manufacturing and Clean Growth priority, and the Combatting Antimicrobial Resistance research priority of the Bioscience for an Integrated Understanding of Health priority of BBSRC's Tackling Strategic Challenges high level objective.
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