Repurposing HDAC inhibitors to enhance ribonuclease 4 and 7 expression and reduce urinary tract infection.
Repurposing HDAC inhibitors to enhance ribonuclease 4 and 7 expression and reduce urinary tract infection.
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重新利用 HDAC 抑制剂来增强核糖核酸酶 4 和 7 的表达并减少尿路感染。
DOI：
10.1073/pnas.2213363120
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发表时间：
2023-01-24
影响因子：
11.1
通讯作者：
Spencer JD
中科院分区：
文献类型：
--
作者：
Schwartz L;Bochter MS;Simoni A;Bender K;de Dios Ruiz Rosado J;Cotzomi-Ortega I;Sanchez-Zamora YI;Becknell B;Linn S;Li B;Santoro N;Eichler T;Spencer JD
随着耐药性细菌的出现，需要新的方法来治疗尿路感染。宿主防御肽作为抗微生物剂具有理想的特性，并可提供抗生素的替代品。核糖核酸酶4和核糖核酸酶7是由肾脏和膀胱产生的宿主防御肽，并对尿路病原菌和耐药性细菌表现出杀菌活性。确定提高其表达的方法可能代表了治疗尿路感染和节省抗生素使用的独特方法。随着耐药性细菌的出现，需要创新的方法来治疗尿路感染。增强抗菌肽的表达可能会提供抗生素的替代品。在这里，我们开发了报告细胞系，并对临床使用的药物进行了高通量筛选，以鉴定促进核糖核酸酶4和7表达（RNase 4和7）的化合物，这些化合物是对耐药泌尿病原体具有抗菌活性的肽。该筛选鉴定了组蛋白脱乙酰酶（HDAC）抑制剂作为有效的RNase 4和RNase 7诱导剂。在原代人肾脏和膀胱细胞中的验证研究证实了泛HDAC抑制剂以及HDAC I类抑制剂MS-275诱导RNA酶4和RNA酶7以保护人肾脏和膀胱细胞免受尿路致病性大肠杆菌的侵害。当我们给小鼠施用MS-275时，RNase 4和7的表达增加，并且小鼠免受急性经尿道E.大肠杆菌攻毒。为了支持这种机制，MS-275处理增加了乙酰化组蛋白H3与RNASE 4和RNASE 7启动子的结合。HDAC I类蛋白的过表达和敲低将HDAC 3鉴定为RNA酶4和7的主要调节剂。这些结果证明了增强RNase 4和RNase 7的保护作用，为重新利用药物作为尿路感染的抗生素保存疗法打开了大门。
With the emergence of antibiotic-resistant bacteria, new approaches are needed for the treatment of urinary tract infections. Host defense peptides have desirable features as antimicrobials and may provide an alternative to antibiotics. Ribonuclease 4 and ribonuclease 7 are host defense peptides produced by the kidney and bladder and exhibit bactericidal activity against uropathogenic bacteria and antibiotic-resistant bacteria. Identifying ways to boost their expression may represent a unique approach to treat urinary tract infections and conserve antibiotic use. With the emergence of antibiotic-resistant bacteria, innovative approaches are needed for the treatment of urinary tract infections. Boosting antimicrobial peptide expression may provide an alternative to antibiotics. Here, we developed reporter cell lines and performed a high-throughput screen of clinically used drugs to identify compounds that boost ribonuclease 4 and 7 expression (RNase 4 and 7), peptides that have antimicrobial activity against antibiotic-resistant uropathogens. This screen identified histone deacetylase (HDAC) inhibitors as effective RNase 4 and RNase 7 inducers. Validation studies in primary human kidney and bladder cells confirmed pan-HDAC inhibitors as well as the HDAC class I inhibitor, MS-275, induce RNase 4 and RNase 7 to protect human kidney and bladder cells from uropathogenic Escherichia coli. When we administered MS-275 to mice, RNase 4 and 7 expression increased and mice were protected from acute transurethral E. coli challenge. In support of this mechanism, MS-275 treatment increased acetylated histone H3 binding to the RNASE4 and RNASE7 promoters. Overexpression and knockdown of HDAC class I proteins identified HDAC3 as a primary regulator of RNase 4 and 7. These results demonstrate the protective effects of enhancing RNase 4 and RNase 7, opening the door to repurposing medications as antibiotic conserving therapeutics for urinary tract infection.
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影响因子：
6.5
作者：
Grabiec AM;Potempa J
通讯作者：
Potempa J
DOI：
10.1038/nrmicro3432
发表时间：
2015-05
期刊：
Nature reviews. Microbiology
影响因子：
--
作者：
Flores-Mireles AL;Walker JN;Caparon M;Hultgren SJ
通讯作者：
Hultgren SJ
影响因子：
82.9
作者：
Chromek, Milan;Slamova, Zuzana;Brauner, Annelie
通讯作者：
Brauner, Annelie
DOI：
10.1136/bmj.i939
发表时间：
2016-03-15
期刊：
BMJ (Clinical research ed.)
影响因子：
--
作者：
Bryce A;Hay AD;Lane IF;Thornton HV;Wootton M;Costelloe C
通讯作者：
Costelloe C
影响因子：
19.6
作者：
通讯作者：
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