Hetero-antagonism of avibactam and sulbactam with cefiderocol in carbapenem-resistant Acinetobacter spp.
| العنوان: | Hetero-antagonism of avibactam and sulbactam with cefiderocol in carbapenem-resistant Acinetobacter spp. |
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| المؤلفون: | Wong O; Center for Applied Biotechnology Studies, Department of Biological Science, College of Natural Sciences and Mathematics, California State University Fullerton, Fullerton, California, USA., Mezcord V; Center for Applied Biotechnology Studies, Department of Biological Science, College of Natural Sciences and Mathematics, California State University Fullerton, Fullerton, California, USA., Lopez C; Center for Applied Biotechnology Studies, Department of Biological Science, College of Natural Sciences and Mathematics, California State University Fullerton, Fullerton, California, USA., Traglia GM; Unidad de Genómica y Bioinformática, Departamento de Ciencias Biológicas, CENUR Litoral Norte, Universidad de la República, Uruguay., Pasteran F; Laboratorio Nacional/Regional de Referencia en Antimicrobianos, Instituto Nacional de Enfermedades Infecciosas, ANLIS Dr. Carlos G. Malbrán, Buenos Aires, Argentina., Tuttobene MR; Área Biología Molecular, Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, Rosario, Argentina.; Instituto de Biología Molecular y Celular de Rosario (IBR, CONICET-UNR), Rosario, Argentina., Corso A; Laboratorio Nacional/Regional de Referencia en Antimicrobianos, Instituto Nacional de Enfermedades Infecciosas, ANLIS Dr. Carlos G. Malbrán, Buenos Aires, Argentina., Tolmasky ME; Center for Applied Biotechnology Studies, Department of Biological Science, College of Natural Sciences and Mathematics, California State University Fullerton, Fullerton, California, USA., Bonomo RA; Research Service and GRECC, Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Cleveland, Ohio, USA.; Departments of Medicine, Pharmacology, Molecular Biology and Microbiology, Biochemistry, Proteomics and Bioinformatics, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.; CWRU-Cleveland VAMC Center for Antimicrobial Resistance and Epidemiology (Case VA CARES), Cleveland, Ohio, USA., Ramirez MS; Center for Applied Biotechnology Studies, Department of Biological Science, College of Natural Sciences and Mathematics, California State University Fullerton, Fullerton, California, USA. |
| المصدر: | BioRxiv : the preprint server for biology [bioRxiv] 2024 Mar 04. Date of Electronic Publication: 2024 Mar 04. |
| نوع المنشور: | Preprint |
| اللغة: | English |
| بيانات الدورية: | Country of Publication: United States NLM ID: 101680187 Publication Model: Electronic Cited Medium: Internet NLM ISO Abbreviation: bioRxiv Subsets: PubMed not MEDLINE |
| مستخلص: | The emergence of Gram-negative bacteria resistant to multiple antibiotics, particularly carbapenem-resistant (CR) Acinetobacter strains, poses a significant threat globally. Despite efforts to develop new antimicrobial therapies, limited progress has been made, with only two drugs-cefiderocol and sulbactam-durlobactam-showing promise for CR- Acinetobacter infections. Cefiderocol, a siderophore cephalosporin, demonstrates promising efficacy in the treatment of Gram-negative infections. However, resistance to cefiderocol has been reported in A. baumannii . Combination therapies, such as cefiderocol with avibactam or sulbactam, show reduced MICs against cefiderocol-non-susceptible strains with in vivo efficacy, although the outcomes can be complex and species-specific. In the present work, the molecular characterization of spontaneous cefiderocol-resistant variants, a CRAB strain displaying antagonism with sulbactam and an A. lwoffii strain showing antagonism with avibactam, were studied. The results reveal intriguing insights into the underlying mechanisms, including mutations affecting efflux pumps, transcriptional regulators, and iron homeostasis genes. Moreover, gene expression analysis reveals significant alterations in outer membrane proteins, iron homeostasis, and β-lactamases, suggesting adaptive responses to selective pressure. Understanding these mechanisms is crucial for optimizing treatment strategies and preventing adverse clinical outcomes. This study highlights the importance of preemptively assessing drug synergies to navigate the challenges posed by antimicrobial resistance in CR- Acinetobacter infections. Competing Interests: Conflicts of Interest: The authors declare no conflict of interest. |
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| معلومات مُعتمدة: | R01 AI100560 United States AI NIAID NIH HHS; R01 AI072219 United States AI NIAID NIH HHS; R01 AI063517 United States AI NIAID NIH HHS; I01 BX001974 United States BX BLRD VA; SC3 GM125556 United States GM NIGMS NIH HHS; R15 AI047115 United States AI NIAID NIH HHS |
| فهرسة مساهمة: | Keywords: Acinetobacter; NDM; antagonism; antimicrobial susceptibility testing (AST); carbapenem-resistance; cefiderocol; diazabicyclooctanes (DBOs); synergy |
| تواريخ الأحداث: | Date Created: 20240318 Latest Revision: 20240325 |
| رمز التحديث: | 20240325 |
| مُعرف محوري في PubMed: | PMC10942374 |
| DOI: | 10.1101/2024.03.04.583376 |
| PMID: | 38496545 |
| قاعدة البيانات: | MEDLINE |
| DOI: | 10.1101/2024.03.04.583376 |
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