Repurposing human kinase inhibitors to create an antibiotic active against drug-resistant Staphylococcus aureus, persisters and biofilms.,Nature Chemistry

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Repurposing human kinase inhibitors to create an antibiotic active against drug-resistant Staphylococcus aureus, persisters and biofilms.
Nature Chemistry ( IF 19.2 ) Pub Date : 2019-12-16 , DOI: 10.1038/s41557-019-0378-7
Philipp Le _{1,

2} , Elena Kunold _{1,

2,

3} , Robert Macsics _{1,

2} , Katharina Rox _{4,

5} , Megan C Jennings ₆ , Ilke Ugur ₇ , Maria Reinecke _{8,

9,

10} , Diego Chaves-Moreno ₁₁ , Mathias W Hackl _{1,

2} , Christian Fetzer _{1,

2} , Franziska A M Mandl _{1,

2} , Johannes Lehmann _{1,

2} , Vadim S Korotkov _{1,

2} , Stephan M Hacker ₁₂ , Bernhard Kuster _{8,

9,

10,

13} , Iris Antes ₇ , Dietmar H Pieper ₁₁ , Manfred Rohde ₁₄ , William M Wuest _{15,

16} , Eva Medina ₁₇ , Stephan A Sieber _{1,

2,

18}

Affiliation

Center for Integrated Protein Science at the Department of Chemistry, Technische Universität München, Garching bei München, Germany.
Chair of Organic Chemistry II, Technische Universität München, Garching bei München, Germany.
SciLifeLab, Department of Oncology-Pathology, Karolinska Institutet, Solna, Sweden.
Department of Chemical Biology, Helmholtz Centre for Infection Research, Braunschweig, Germany.
German Centre for Infection Research, Partner Site Braunschweig-Hannover, Hannover, Germany.
Department of Chemistry, Temple University, Philadelphia, PA, USA.
Center for Integrated Protein Science, TUM School of Life Sciences, Technische Universität München, Freising, Germany.
Chair of Proteomics and Bioanalytics, Technische Universität München, Freising, Germany.
German Cancer Consortium, Partner Site Munich, Munich, Germany.
German Cancer Research Center, Heidelberg, Germany.
Microbial Interactions and Processes Research Group, Helmholtz Centre for Infection Research, Braunschweig, Germany.
Department of Chemistry, Technische Universität München, Garching bei München, Germany.
Center for Integrated Protein Science Munich, Garching bei München, Germany.
Central Facility for Microscopy, Helmholtz Centre for Infection Research, Braunschweig, Germany.
Department of Chemistry, Emory University, Atlanta, GA, USA.
Emory Antibiotic Resistance Center, Emory School of Medicine, Atlanta, GA, USA.
Infection Immunology Research Group, Helmholtz Centre for Infection Research, Braunschweig, Germany.
Helmholtz Institute for Pharmaceutical Research Saarland, Helmholtz Centre for Infection Research, Saarbrücken, Germany.

New drugs are desperately needed to combat methicillin-resistant Staphylococcus aureus (MRSA) infections. Here, we report screening commercial kinase inhibitors for antibacterial activity and found the anticancer drug sorafenib as major hit that effectively kills MRSA strains. Varying the key structural features led to the identification of a potent analogue, PK150, that showed antibacterial activity against several pathogenic strains at submicromolar concentrations. Furthermore, this antibiotic eliminated challenging persisters as well as established biofilms. PK150 holds promising therapeutic potential as it did not induce in vitro resistance, and shows oral bioavailability and in vivo efficacy. Analysis of the mode of action using chemical proteomics revealed several targets, which included interference with menaquinone biosynthesis by inhibiting demethylmenaquinone methyltransferase and the stimulation of protein secretion by altering the activity of signal peptidase IB. Reduced endogenous menaquinone levels along with enhanced levels of extracellular proteins of PK150-treated bacteria support this target hypothesis. The associated antibiotic effects, especially the lack of resistance development, probably stem from the compound's polypharmacology.

中文翻译：

重新利用人类激酶抑制剂来产生针对耐药金黄色葡萄球菌、持久菌和生物膜的抗生素活性。

迫切需要新药来对抗耐甲氧西林金黄色葡萄球菌 (MRSA) 感染。在这里，我们报告了筛选商业激酶抑制剂的抗菌活性，并发现抗癌药物索拉非尼是有效杀死 MRSA 菌株的主要药物。改变关键结构特征导致鉴定出一种有效的类似物 PK150，它在亚微摩尔浓度下对几种致病菌株表现出抗菌活性。此外，这种抗生素消除了具有挑战性的残留物以及已形成的生物膜。 PK150 具有广阔的治疗潜力，因为它不会诱导体外耐药性，并显示出口服生物利用度和体内功效。使用化学蛋白质组学分析作用模式揭示了几个目标，其中包括通过抑制去甲基甲萘醌甲基转移酶来干扰甲萘醌生物合成，以及通过改变信号肽酶IB的活性来刺激蛋白质分泌。 PK150 处理的细菌内源性甲基萘醌水平降低以及细胞外蛋白水平提高支持了这一目标假设。相关的抗生素作用，尤其是不产生耐药性，可能源于该化合物的多药理学。

更新日期：2019-12-17

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