دورية أكاديمية
Structure-activity relationships of actively FhuE transported rifabutin derivatives with potent activity against Acinetobacter baumannii.
| العنوان: | Structure-activity relationships of actively FhuE transported rifabutin derivatives with potent activity against Acinetobacter baumannii. |
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| المؤلفون: | Maingot M; Univ. Lille, Inserm, Institut Pasteur de Lille, U1177 - Drugs and Molecules for Living Systems, 59000, Lille, France., Bourotte M; BioVersys SAS, 1 rue du Professeur Calmette, 59000, Lille, France., Vetter AC; Department of Chemical Biology, Helmholtz Centre for Infection Research, Inhoffenstraße 7, 38124, Braunschweig, Germany., Schellhorn B; BioVersys AG, 60C Hochbergerstrasse, 4057, Basel, Switzerland., Antraygues K; Univ. Lille, Inserm, Institut Pasteur de Lille, U1177 - Drugs and Molecules for Living Systems, 59000, Lille, France., Scherer H; Univ. Lille, Inserm, Institut Pasteur de Lille, U1177 - Drugs and Molecules for Living Systems, 59000, Lille, France., Gitzinger M; BioVersys AG, 60C Hochbergerstrasse, 4057, Basel, Switzerland., Kemmer C; BioVersys AG, 60C Hochbergerstrasse, 4057, Basel, Switzerland., Dale GE; BioVersys AG, 60C Hochbergerstrasse, 4057, Basel, Switzerland., Defert O; BioVersys SAS, 1 rue du Professeur Calmette, 59000, Lille, France., Lociuro S; BioVersys AG, 60C Hochbergerstrasse, 4057, Basel, Switzerland., Brönstrup M; Department of Chemical Biology, Helmholtz Centre for Infection Research, Inhoffenstraße 7, 38124, Braunschweig, Germany., Willand N; Univ. Lille, Inserm, Institut Pasteur de Lille, U1177 - Drugs and Molecules for Living Systems, 59000, Lille, France. Electronic address: nicolas.willand@univ-lille.fr., Trebosc V; BioVersys AG, 60C Hochbergerstrasse, 4057, Basel, Switzerland. Electronic address: vincent.trebosc@bioversys.com. |
| المصدر: | European journal of medicinal chemistry [Eur J Med Chem] 2023 Apr 05; Vol. 252, pp. 115257. Date of Electronic Publication: 2023 Mar 16. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: Editions Scientifiques Elsevier Country of Publication: France NLM ID: 0420510 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1768-3254 (Electronic) Linking ISSN: 02235234 NLM ISO Abbreviation: Eur J Med Chem Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: Paris : Editions Scientifiques Elsevier Original Publication: Paris, S.E.C.T. [etc.] |
| مواضيع طبية MeSH: | Acinetobacter baumannii* , Staphylococcal Infections*/drug therapy, Humans ; Rifabutin/pharmacology ; Anti-Bacterial Agents/pharmacology ; Anti-Bacterial Agents/therapeutic use ; Structure-Activity Relationship ; Microbial Sensitivity Tests ; Drug Resistance, Multiple, Bacterial |
| مستخلص: | 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. Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Birgit Schellhorn, Vincent Trebosc, Marc Gitzinger, Glenn E. Dale, Sergio Lociuro are Bioversys AG employees. Marc Gitzinger is a shareholder of Bioversys AG. Marilyne Bourotte and Olivier Defert were BioVersys SAS employees. Nicolas Willand is consultant for Bioversys AG. The other authors declare that they have no competing interests. (Copyright © 2023 Elsevier Masson SAS. All rights reserved.) |
| فهرسة مساهمة: | Keywords: Ansamycin antibiotics; Carbapenem-resistant A. baumannii; Compound uptake; Minimum inhibitory concentration; Rifabutin; Structure-activity relationships |
| المشرفين على المادة: | 1W306TDA6S (Rifabutin) 0 (Anti-Bacterial Agents) |
| تواريخ الأحداث: | Date Created: 20230322 Date Completed: 20230414 Latest Revision: 20230414 |
| رمز التحديث: | 20231215 |
| DOI: | 10.1016/j.ejmech.2023.115257 |
| PMID: | 36948128 |
| قاعدة البيانات: | MEDLINE |
Full Text Finder | تدمد: | 1768-3254 |
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| DOI: | 10.1016/j.ejmech.2023.115257 |