Altering glycopeptide antibiotic biosynthesis through mutasynthesis allows incorporation of fluorinated phenylglycine residues†

IF 4.2 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY RSC Chemical Biology Pub Date : 2024-08-12 DOI:10.1039/D4CB00140K
Irina Voitsekhovskaia, Y. T. Candace Ho, Christoph Klatt, Anna Müller, Daniel L. Machell, Yi Jiun Tan, Maxine Triesman, Mara Bingel, Ralf B. Schittenhelm, Julien Tailhades, Andreas Kulik, Martin E. Maier, Gottfried Otting, Wolfgang Wohlleben, Tanja Schneider, Max Cryle and Evi Stegmann
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Abstract

Glycopeptide antibiotics (GPAs) are peptide natural products used as last resort treatments for antibiotic resistant bacterial infections. They are produced by the sequential activities of a linear nonribosomal peptide synthetase (NRPS), which assembles the heptapeptide core of GPAs, and cytochrome P450 (Oxy) enzymes, which perform a cascade of cyclisation reactions. The GPAs contain proteinogenic and nonproteinogenic amino acids, including phenylglycine residues such as 4-hydroxyphenylglycine (Hpg). The ability to incorporate non-proteinogenic amino acids in such peptides is a distinctive feature of the modular architecture of NRPSs, with each module selecting and incorporating a desired amino acid. Here, we have exploited this ability to produce and characterise GPA derivatives containing fluorinated phenylglycine (F-Phg) residues through a combination of mutasynthesis, biochemical, structural and bioactivity assays. Our data indicate that the incorporation of F-Phg residues is limited by poor acceptance by the NRPS machinery, and that the phenol moiety normally present on Hpg residues is essential to ensure both acceptance by the NRPS and the sequential cyclisation activity of Oxy enzymes. The principles learnt here may prove useful for the future production of GPA derivatives with more favourable properties through mixed feeding mutasynthesis approaches.

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通过突变合成改变糖肽抗生素的生物合成,可以加入含氟苯甘氨酸残基。
糖肽类抗生素(GPAs)是一种肽类天然产物,是治疗抗生素耐药细菌感染的最后手段。它们是由线性非核糖体肽合成酶(NRPS)和细胞色素 P450(Oxy)酶的连续活动产生的,前者负责组装 GPAs 的七肽核心,后者则负责执行一连串的环化反应。GPAs 含有致蛋白氨基酸和非致蛋白氨基酸,包括苯甘氨酸残基,如 4-羟基苯甘氨酸(Hpg)。在这种肽中加入非蛋白源氨基酸的能力是 NRPSs 模块化结构的一个显著特点,每个模块都能选择并加入所需的氨基酸。在这里,我们利用这种能力,通过结合突变合成、生化、结构和生物活性测定,生产出了含有氟化苯甘氨酸(F-Phg)残基的 GPA 衍生物,并对其进行了表征。我们的数据表明,F-Phg 残基的结合受到 NRPS 机制接受能力差的限制,而通常存在于 Hpg 残基上的苯酚分子对于确保 NRPS 的接受能力和 Oxy 酶的顺序环化活性至关重要。这里所学到的原理可能有助于今后通过混合进料突变合成法生产出具有更有利特性的 GPA 衍生物。
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来源期刊
CiteScore
6.10
自引率
0.00%
发文量
128
审稿时长
10 weeks
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