論文 - 詳細
| RRC ID | 78962 |
|---|---|
| 著者 | Lorenzo Bernacchia, Antoine Paris, Arya Gupta, Alexandra A. Moores, Neil M. Kad |
| タイトル | Identification of the target and mode of action for the prokaryotic nucleotide excision repair inhibitor ATBC |
| ジャーナル | Bioscience Reports |
| Abstract |
In bacteria, nucleotide excision repair (NER) plays a major role in repairing DNA damage from a wide variety of sources. Therefore, its inhibition offers potential to develop a new antibacterial in combination with adjuvants, such as UV light. To date, only one known chemical inhibitor of NER is 2-(5-amino-1,3,4-thiadiazol-2-yl)benzo(f)chromen-3-one (ATBC) exists and targets Mycobacterium tuberculosis NER. To enable the design of future drugs, we need to understand its mechanism of action. To determine the mechanism of action, we used in silico structure-based prediction, which identified the ATP-binding pocket of Escherichia coli UvrA as a probable target. Growth studies in E. coli showed it was nontoxic alone, but able to impair growth when combined with DNA-damaging agents, and as we predicted, it reduced by an approximately 70% UvrA’s ATPase rate. Since UvrA’s ATPase activity is necessary for effective DNA binding, we used single-molecule microscopy to directly observe DNA association. We measured an approximately sevenfold reduction in UvrA molecules binding to a single molecule of dsDNA suspended between optically trapped beads. These data provide a clear mechanism of action for ATBC, and show that targeting UvrA’s ATPase pocket is effective and ATBC provides an excellent framework for the derivation of more soluble inhibitors that can be tested for activity. |
| 巻・号 | 42 |
| 公開日 | 2022-6-30 |
| DOI | 10.1042/bsr20220403 |
| PMID | 35546304 |
| PMC | PMC9152706 |
| MeSH | Adenosine Triphosphatases / genetics DNA / metabolism DNA Damage DNA Repair DNA, Bacterial / genetics DNA, Bacterial / metabolism Escherichia coli* / genetics Escherichia coli* / metabolism Escherichia coli Proteins* / genetics Escherichia coli Proteins* / metabolism Ultraviolet Rays |
| IF | 2.942 |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | X(Twitter) |
| 各媒体での言及数の合計 | 4 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| 原核生物(大腸菌) | JW4019-KC |