Investigation of tailoring steps in antibiotic peptide biosynthesis Jessica Peate, Yaoyu Ding, Gustavo Perez-Ortiz and Sarah M. Barry King's College London, UK Antimicrobial resistance (AMR) is a critical global health concern accelerated by theoveruse and misuse of antibiotic compounds. A potential solution to overcome this issueis to develop new forms of therapy. This is more reliably done by derivatising theantibiotics we already use clinically, to maintain or improve their activity whilst becomingunrecognisable to the infection. Biosynthetic enzymes may provide an easy and environmentallyfriendly way of derivatising these structures. Understanding how these enzymesperform complicated chemical modifications resulting in significant changes in biological activity will aid in the development of new biocatalysts. Tuberculosis (TB) is one of the most lethal infections of the modern world. With manystrains gaining resistance to commonly used antibiotics, it is imperative that alternativecompounds be studied. The cyclic non-ribosomal peptide known as rufomycin, is a naturalproduct that has known activity against TB. It is reported to inhibit ClpC1 proteolysisboth in Mycobacterium tuberculosis and Mycobacterium abscessus . 1 However, rufomycin has poor pharmacological characteristics. Understanding the biosynthesis of rufomycin’s important moieties for anti-TB activity could aid in the development of derivatives with more favourable qualities. 2 The goal of this study is to provide structural and functional insight into biosynthetic tailoring enzymes of rufomycin biosynthesis. Here we focused particularly on the late-stage functionalisation of the cyclic peptide by two cytochrome P450s responsible for regio and stereoselective oxidations which are vital to the biological activity of rufomycins. 3 References 1. Han, X. Liu, L. Zhang, R. Quinn and Y. Feng, Natural Product Reports , 2022, 39 , 77-89. 2. Ma, H. Huang, Y. Xie, Z. Liu, J. Zhao, C. Zhang, Y. Jia, Y. Zhang, H. Zhang, T. Zhang and J. Ju, Nature Communications , 2017, 8 , 391. 3. Perez Ortiz, J. D. Sidda, E. L. De Los Santos, C. B. Hubert and S. M. Barry, Chemical Communications , 2021, 57 , 11795– 11798.
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