Kramer Jil-Christine, Wuisan Zerlina G, Mettal Ute, Marner Michael, Schäberle Till F
Natural Product Research Department, Institute for Insect Biotechnology, Justus-Liebig-University Giessen, Ohlebergsweg 12, 35392 Giessen, Germany.
Natural Product Department; Fraunhofer-Institute for Molecular Biology and Applied Ecology (IME), Ohlebergsweg 12, 35392 Giessen, Germany.
ACS Omega. 2025 Apr 30;10(18):18356-18363. doi: 10.1021/acsomega.4c10307. eCollection 2025 May 13.
The ribosomally synthesized and post-translationally modified peptide (RiPP) darobactin A is a promising new antibiotic candidate with anti-Gram-negative activity inflicted by the inhibition of the novel target BamA. Genome mining revealed many putative darobactin producer strains, but a limited number of compound modification options. In this study, the amber stop codon suppression technique was used to integrate non-canonical amino acids into the bicyclic heptapeptide, creating new darobactin derivatives. The C-terminal phenylalanine was replaced by non-canonical phenylalanine derivatives with different substituents. Darobactin A F7F, featuring a fluorine atom in the para position of the C-terminal phenylalanine, was purified to enable structure validation by NMR. Activity assays revealed antimicrobial potency against selected Gram-negative strains comparable to darobactin A.
核糖体合成及翻译后修饰肽（RiPP）达罗巴汀A是一种有前景的新型抗生素候选物，通过抑制新型靶点BamA发挥抗革兰氏阴性菌活性。基因组挖掘揭示了许多潜在的达罗巴汀产生菌，但化合物修饰选项有限。在本研究中，利用琥珀色终止密码子抑制技术将非天然氨基酸整合到双环七肽中，从而产生新的达罗巴汀衍生物。C末端苯丙氨酸被具有不同取代基的非天然苯丙氨酸衍生物所取代。在C末端苯丙氨酸的对位带有氟原子的达罗巴汀A F7F被纯化，以便通过核磁共振进行结构验证。活性测定表明，其对所选革兰氏阴性菌株的抗菌效力与达罗巴汀A相当。
