Evaluation of Expanded 2-Aminobenzothiazole Library for Inhibition of Pseudomonas aeruginosa Virulence Phenotypes.
| العنوان: | Evaluation of Expanded 2-Aminobenzothiazole Library for Inhibition of Pseudomonas aeruginosa Virulence Phenotypes. |
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| المؤلفون: | Fihn CA; Department of Medicinal Chemistry, University of Minnesota, 308 Harvard Street SE, Minneapolis, Minnesota 55455, United States., Lembke HK; Department of Chemistry, University of Minnesota, 207 Pleasant Street SE, Minneapolis, Minnesota 55454, United States., Gaulin J; The Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, United States., Bouchard P; NMX Research and Solution Inc., 500 Cartier Boulevard W., Suite 6000, Laval, Quebec, Canada, H1Y 2R1., Villarreal AR; Department of Microbiology & Immunology, University of Minnesota, 689 23rd Ave Se Minneapolis, Minnesota 55455, United States., Penningroth MR; Department of Microbiology & Immunology, University of Minnesota, 689 23rd Ave Se Minneapolis, Minnesota 55455, United States., Crone KK; Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, 321 Church Street SE, Minneapolis, Minnesota 55455, United States., Vogt GA; Department of Microbiology & Immunology, University of Minnesota, 689 23rd Ave Se Minneapolis, Minnesota 55455, United States., Gilbertsen AJ; Department of Microbiology & Immunology, University of Minnesota, 689 23rd Ave Se Minneapolis, Minnesota 55455, United States., Ayotte Y; NMX Research and Solution Inc., 500 Cartier Boulevard W., Suite 6000, Laval, Quebec, Canada, H1Y 2R1., de Oliveira LC; NMX Research and Solution Inc., 500 Cartier Boulevard W., Suite 6000, Laval, Quebec, Canada, H1Y 2R1., Serrano-Wu MH; 3 Point Bio LLC, 245 Main Street, Cambridge, Massachusetts 02142, United States., Drouin N; NMX Research and Solution Inc., 500 Cartier Boulevard W., Suite 6000, Laval, Quebec, Canada, H1Y 2R1., Hung DT; The Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, United States., Hunter RC; Department of Microbiology & Immunology, University of Minnesota, 689 23rd Ave Se Minneapolis, Minnesota 55455, United States., Carlson EE; Department of Medicinal Chemistry, University of Minnesota, 308 Harvard Street SE, Minneapolis, Minnesota 55455, United States.; Department of Chemistry, University of Minnesota, 207 Pleasant Street SE, Minneapolis, Minnesota 55454, United States.; Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, 321 Church Street SE, Minneapolis, Minnesota 55455, United States. |
| المصدر: | BioRxiv : the preprint server for biology [bioRxiv] 2024 Jan 10. Date of Electronic Publication: 2024 Jan 10. |
| 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: | Bacterial resistance to antibiotics is a rapidly increasing threat to human health. New strategies to combat resistant organisms are desperately needed. One potential avenue is targeting two-component systems, which are the main bacterial signal transduction pathways used to regulate development, metabolism, virulence, and antibiotic resistance. These systems consist of a homodimeric membrane-bound sensor histidine kinase, and a cognate effector, the response regulator. The high sequence conservation in the catalytic and adenosine triphosphate-binding (CA) domain of histidine kinases and their essential role in bacterial signal transduction could enable broad-spectrum antibacterial activity. Through this signal transduction, histidine kinases regulate multiple virulence mechanisms including toxin production, immune evasion, and antibiotic resistance. Targeting virulence, as opposed to development of bactericidal compounds, could reduce evolutionary pressure for acquired resistance. Additionally, compounds targeting the CA domain have the potential to impair multiple two-component systems that regulate virulence in one or more pathogens. We conducted structure-activity relationship studies of 2-aminobenzothiazole-based inhibitors designed to target the CA domain of histidine kinases. We found these compounds have anti-virulence activities in Pseudomonas aeruginosa , reducing motility phenotypes and toxin production associated with the pathogenic functions of this bacterium. |
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| معلومات مُعتمدة: | R01 GM134538 United States GM NIGMS NIH HHS; T32 GM008347 United States GM NIGMS NIH HHS |
| تواريخ الأحداث: | Date Created: 20230519 Latest Revision: 20240210 |
| رمز التحديث: | 20240210 |
| مُعرف محوري في PubMed: | PMC10187220 |
| DOI: | 10.1101/2023.05.02.539119 |
| PMID: | 37205454 |
| قاعدة البيانات: | MEDLINE |
| DOI: | 10.1101/2023.05.02.539119 |
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