Ko Yoo-Sung, Gu Di, Lee Amy, Marzooqi Dunya Al, Zhang Wenjun
Department of Chemical and Biomolecular Engineering, University of California Berkeley, Berkeley, California 94720, United States.
Department of Chemistry, University of California Berkeley, Berkeley, California 94720, United States.
ACS Sustain Chem Eng. 2025 Jul 14;13(27):10556-10562. doi: 10.1021/acssuschemeng.5c03104. Epub 2025 Jun 30.
Salivabactin, a newly discovered hybrid polyketide/nonribosomal peptide (PK/NRP) antibiotic with a unique scaffold, exhibits potent activity against Gram-positive pathogens such as . Despite its promising bioactivity, the low yield of the native producer (SAL) limits further investigation into salivabactin's mode of action and pharmaceutical applications. Here, we report the first heterologous production of salivabactin in . The biosynthetic genes were co-expressed in , followed by optimizations in gene expression and precursor feeding to improve biosynthetic efficiency. Additional metabolic engineering strategies, including the knockout of a 4-hydroxybenzoic acid (4-HBA) exporter to increase intracellular precursor availability and overexpression of a multidrug exporter, significantly improved the titer. The final engineered strain achieved a titer of 5.48 mg/L of salivabactin, representing a 22-fold increase in production compared to the native SAL strain. This work establishes as a scalable microbial platform for salivabactin production and demonstrates its potential as a versatile chassis for the biosynthesis of complex PK/NRP antibiotics.
唾液菌素是一种新发现的具有独特骨架的杂合聚酮化合物/非核糖体肽（PK/NRP）抗生素，对革兰氏阳性病原体如……具有强大活性。尽管其具有有前景的生物活性，但天然产生菌（SAL）的低产量限制了对唾液菌素作用模式和药物应用的进一步研究。在此，我们报道了唾液菌素在……中的首次异源生产。生物合成基因在……中共同表达，随后对基因表达和前体供应进行优化以提高生物合成效率。额外的代谢工程策略，包括敲除4-羟基苯甲酸（4-HBA）输出蛋白以增加细胞内前体可用性以及过表达一种多药输出蛋白，显著提高了产量。最终的工程菌株唾液菌素产量达到5.48 mg/L，与天然SAL菌株相比产量提高了22倍。这项工作确立了……作为唾液菌素生产的可扩展微生物平台，并证明了其作为复杂PK/NRP抗生素生物合成通用底盘的潜力。
