Repurposing Acitretin as an Antipseudomonal Agent Targeting the Pseudomonas aeruginosa Iron-Regulated Heme Oxygenase
| العنوان: | Repurposing Acitretin as an Antipseudomonal Agent Targeting the Pseudomonas aeruginosa Iron-Regulated Heme Oxygenase |
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| المؤلفون: | Angela Wilks, Fengtian Xue, Elizabeth Robinson |
| المصدر: | Biochemistry. 60:689-698 |
| بيانات النشر: | American Chemical Society (ACS), 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | chemistry.chemical_classification, 0303 health sciences, Oxygenase, Siderophore, Pseudomonas aeruginosa, 030302 biochemistry & molecular biology, medicine.disease_cause, Biochemistry, Acitretin, Heme oxygenase, 03 medical and health sciences, chemistry.chemical_compound, Enzyme, chemistry, medicine, IC50, Heme, medicine.drug |
| الوصف: | Iron is an essential micronutrient for the survival and virulence of the bacterial pathogen Pseudomonas aeruginosa. To overcome iron withholding and successfully colonize a host, P. aeruginosa uses a variety of mechanisms to acquire iron, including the secretion of high-affinity iron chelators (siderophores) or the uptake and utilization of heme. P. aeruginosa heme oxygenase (HemO) plays pivotal roles in heme sensing, uptake, and utilization and has emerged as a therapeutic target for the development of antipseudomonal agents. Using a high-throughput fluorescence quenching assay combined with minimum inhibitory concentration measurements, we screened the Selleck Bioactive collection of 2100 compounds and identified acitretin, a Food and Drug Administration-approved oral retinoid, as a potent and selective inhibitor of HemO. Acitretin binds to HemO with a KD value of 0.10 ± 0.02 μM and inhibits the growth of P. aeruginosa PAO1 with an IC50 of 70 ± 18 μg/mL. In addition, acitretin showed good selectivity for HemO, which uniquely generates BVIXβ/δ, over human heme oxygenase (hHO1) and other BVIXα-producing homologues such as the heme oxygenases from Neisseria meningitidis (nmHO) and Acinetobacter baumannii (abHO). The binding of acitretin within the HemO active site was confirmed by 1H-15N heteronuclear single-quantum coherence nuclear magnetic resonance, and molecular modeling provided further insight into potential interactions of acitretin with residues specific for orienting heme in the β/δ selective HemO. Moreover, at 20 μM, acitretin inhibited the enzymatic activity of HemO in P. aeruginosa cells by >60% and effectively blocked the ability of P. aeruginosa to sense and acquire heme as demonstrated in the β-galactosidase transcriptional reporter assay. |
| تدمد: | 1520-4995 0006-2960 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_________::197bf1488c0ba2af13acee39c2a7ba08 https://doi.org/10.1021/acs.biochem.0c00895 |
| حقوق: | CLOSED |
| رقم الأكسشن: | edsair.doi...........197bf1488c0ba2af13acee39c2a7ba08 |
| قاعدة البيانات: | OpenAIRE |
Find this issue from the American Chemical Society | تدمد: | 15204995 00062960 |
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