Department of Chemical Biology Helmholtz Centre for Infection Research, Inhoffenstrasse 7, 38124 Braunschweig, Germany.
Institute for Organic Chemistry, Technical University of Braunschweig, Hagenring 30, 38106 Braunschweig, Germany.
J Med Chem. 2021 Oct 28;64(20):15440-15460. doi: 10.1021/acs.jmedchem.1c01482. Epub 2021 Oct 8.
The development of novel drugs against Gram-negative bacteria represents an urgent medical need. To overcome their outer cell membrane, we synthesized conjugates of antibiotics and artificial siderophores based on the MECAM core, which are imported by bacterial iron uptake systems. Structures, spin states, and iron binding properties were predicted using density functional theory. The capability of MECAM to function as an effective artificial siderophore in was proven in microbiological growth recovery and bioanalytical assays. Following a linker optimization focused on transport efficiency, five β-lactam and one daptomycin conjugates were prepared. The most potent conjugate showed growth inhibition of Gram-positive and Gram-negative multidrug-resistant pathogens at nanomolar concentrations. The uptake pathway of MECAMs was deciphered by knockout mutants and highlighted the relevance of FepA, CirA, and Fiu. Resistance against was mediated by a mutation in the gene encoding ExbB, which is involved in siderophore transport.
开发针对革兰氏阴性菌的新型药物是一项紧迫的医疗需求。为了克服它们的外细胞膜，我们基于 MECAM 核心合成了抗生素和人工铁载体的缀合物，这些缀合物可以被细菌铁摄取系统摄取。使用密度泛函理论预测了结构、自旋态和铁结合特性。在微生物生长恢复和生物分析测定中证明了 MECAM 作为有效人工铁载体的功能。在针对转运效率的接头优化之后，制备了五个β-内酰胺和一个达托霉素缀合物。最有效的缀合物 以纳摩尔浓度抑制革兰氏阳性和革兰氏阴性多药耐药病原体的生长。通过敲除突变体解析了 MECAMs 的摄取途径，并强调了 FepA、CirA 和 Fiu 的相关性。对 的耐药性是由编码 ExbB 的基因中的突变介导的，该基因参与铁载体转运。
