Synthesis of Derivatives of the Antibiotic Albicidin: The N-Terminal Fragment as Key to Control Potency and Resistance Mediated by the Binding Protein AlbA.

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Tác giả: Dmitry Ghilarov, Leela B Ghimire, Kay Hommernick, Simone Kosol, Marcel Kulike-Koczula, Andi Mainz, Nicole Sattler, Maria Seidel, Roderich D Süssmuth, John B Weston, Lieby Zborovsky

Ngôn ngữ: eng

Ký hiệu phân loại: 668.374 Synthetic gum and resin

Thông tin xuất bản: Germany : Chemistry (Weinheim an der Bergstrasse, Germany) , 2025

Mô tả vật lý:

Bộ sưu tập: NCBI

ID: 741031

The peptide albicidin represents a highly promising lead structure which is a first-in-class antibiotic with remarkable potency against gram-negative bacteria. Past efforts in the synthesis of albicidin analogs focused on increasing hydrophilicity, broadening of the antibacterial profile and overcoming resistance. Herein, we present synthetic albicidin derivatives with variations in the N-terminal building block and characterize their antibacterial activity and DNA gyrase inhibition. Furthermore, we show that the N-terminus of albicidin greatly affects binding to the resistance factor AlbAL. This transcription regulator senses albicidin and triggers the biosynthesis of the binding protein AlbAS, thus reducing the free concentration of the antibiotic. Here we demonstrate uncoupling of the binding event from transcription activation for some derivatives, and even a few derivatives seemed insensitive to sequestration by AlbA. This approach could be a strategy to develop albicidin analogs escaping AlbA resistance.
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