Bacteria assemble complex molecules that can kill pests, fight infections, or modulate the immune system—and this project will figure out how to make them swap parts to create new variants. The problem is that these molecules, called hybrid polyketide-nonribosomal peptides, are structurally so intricate that chemically modifying them is expensive, energy-intensive, and relies on petrochemicals. Nature, however, already mixes and matches the enzyme modules that build them. This research focuses on a specific class of these molecules—histone deacetylase (HDAC) inhibitors—and aims to understand how a conserved enzyme module (a polyketide synthase) can productively engage with different partner modules (nonribosomal peptide synthetases) to generate diverse products. If successful, the work will enable bioengineering approaches that produce optimised drug or agrochemical analogues through simple fermentation, using plant-derived feedstocks instead of petroleum. This could lower manufacturing costs, reduce environmental harm, and make sustainable production of complex therapeutics or crop-protection chemicals feasible. The project is fundamental bioscience—it asks how evolution creates molecular diversity—but the engineering tools it develops could directly replace polluting chemical synthesis with cleaner biological manufacturing.
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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 understand how promiscuous interactions between a conserved modular polyketide synthase (PKS) and various nonribosomal peptide synthetases (NRPSs) enables natural combinatorial biosynthesis of a medically important class of histone deacetylase (HDAC) inhibitors. We will test our understanding by engineering production of a novel HDAC inhibitor analogue. The specific objectives of our proposal are: Structurally characterise inter-subunit interactions enabling productive PKS-NRPS engagement in FR901375 biosynthesis Investigate crosstalk between HDAC inhibitor PKS and enacyloxin IIa NRPS subunits in vitro Produce an HDAC inhibitor analogue in vivo Provide interdisciplinary training and career development to a promising young researcher The knowledge gained from this interdisciplinary research will enable the development of bioengineering approaches to rational alteration of hybrid polyketide-nonribosomal peptide natural products, which often require structural modification to optimise them for therapeutic or agricultural application. Structural modification of polyketide-nonribosomal peptide analogues 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 polyketide-nonribosomal peptide hybrids 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 Bioscience for an Integrated Understanding of Health priority of BBSRC's Tackling Strategic Challenges high level objective.
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