Maingot M, Bourotte M, Vetter A C, Schellhorn B, Antraygues K, Scherer H, Gitzinger M, Kemmer C, Dale G E, Defert O, Lociuro S, Brönstrup M, Willand N, Trebosc V
Univ. Lille, Inserm, Institut Pasteur de Lille, U1177 - Drugs and Molecules for Living Systems, 59000, Lille, France.
BioVersys SAS, 1 rue du Professeur Calmette, 59000, Lille, France.
Eur J Med Chem. 2023 Apr 5;252:115257. doi: 10.1016/j.ejmech.2023.115257. Epub 2023 Mar 16.
Hospital-acquired infections are on the rise and represent both, a clinical and financial burden. With resistance emerging and an ever-dwindling armamentarium at hand, infections caused by Acinetobacter baumannii are particularly problematic, since these bacteria have a high level of resistance and resilience to traditional and even last-resort antibiotics. The antibiotic rifabutin was recently found to show potent in vitro and in vivo activity against extensively drug resistant A. baumannii. Building on this discovery, we report on the synthesis and activity of rifabutin analogs, with a focus on N-functionalization of the piperidine ring. The antimicrobial testing uncovered structure activity relationships (SAR) for A. baumannii that were not reflected in Staphylococcus aureus. The cellular activity did not correlate with cell-free transcription inhibition, but with bacterial intracellular compound accumulation. Mass spectrometry-based accumulation studies confirmed the involvement of the siderophore receptor FhuE in active compound translocation at low concentrations, and they showed a strong impact of the culture medium on the accumulation of rifabutin. Overall, the study underlines the structural feature required for strong accumulation of rifabutin in A. baumannii and identifies analogs as or more potent than rifabutin against A. baumannii.
医院获得性感染正在增加，并且构成了临床和经济负担。随着耐药性的出现以及可用药物日益减少，鲍曼不动杆菌引起的感染尤其成问题，因为这些细菌对传统抗生素甚至最后手段抗生素都具有高度耐药性和恢复力。最近发现抗生素利福布汀对广泛耐药的鲍曼不动杆菌具有强大的体外和体内活性。基于这一发现，我们报告了利福布汀类似物的合成及活性，重点是哌啶环的N-官能化。抗菌测试揭示了鲍曼不动杆菌的构效关系（SAR），而金黄色葡萄球菌中未体现这种关系。细胞活性与无细胞转录抑制无关，而是与细菌细胞内化合物积累有关。基于质谱的积累研究证实，铁载体受体FhuE在低浓度下参与活性化合物的转运，并且它们显示培养基对利福布汀的积累有很大影响。总体而言，该研究强调了利福布汀在鲍曼不动杆菌中强烈积累所需的结构特征，并鉴定出比利福布汀对鲍曼不动杆菌更有效或效力相当的类似物。
