Complete biosynthesis of penicillin G in Nicotiana benthamiana

Abdul Rawoof, Yen Tung Lin, Sanjeevan Rajendran, Gaelle Antoine, Sameera Jayasundara, Yingqi Cai, Digar Singh, Payton Whitehead, Haley Dornberger, Sonya Mall, Ana P. Alonso, Michael C. Carroll, Elizabeth Skellam, Kent D. Chapman
2026 · doi:10.64898/2026.05.08.723852
preprint OA: closed CC-BY-NC-4.0
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Abstract

Commercial penicillin production has relied on microbial fermentation for more than 80 years. Here, we engineered the plant, Nicotiana benthamiana , to produce penicillin G in its leaves by transient expression of up to seven fungal biosynthetic genes. Remarkably, all recombinant proteins localize to the analogous subcellular compartments without engineering signal peptide sequences or post-translational modification sites. Although non-ribosomal peptide synthetases occur widely in fungi and bacteria to produce a plethora of specialized metabolites, their evolutionary distribution does not extend to plants. Our results now open a new metabolic frontier for natural product synthesis, and offer possibilities to address global health concerns through an alternative biotechnology platform for fungal-derived pharmaceutical production.
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Abstract Commercial penicillin production has relied on microbial fermentation for more than 80 years. Here, we engineered the plant, Nicotiana benthamiana, to produce penicillin G in its leaves by transient expression of up to seven fungal biosynthetic genes. Remarkably, all recombinant proteins localize to the analogous subcellular compartments without engineering signal peptide sequences or post-translational modification sites. Although non-ribosomal peptide synthetases occur widely in fungi and bacteria to produce a plethora of specialized metabolites, their evolutionary distribution does not extend to plants. Our results now open a new metabolic frontier for natural product synthesis, and offer possibilities to address global health concerns through an alternative biotechnology platform for fungal-derived pharmaceutical production. Competing Interest Statement The authors have declared no competing interest.

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License: CC-BY-NC-4.0