An Aromatic Hydroxyamide Attenuates Multiresistant Staphylococcus aureus Toxin Expression.
An Aromatic Hydroxyamide Attenuates Multiresistant Staphylococcus aureus Toxin Expression.
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DOI：
10.1002/chem.201503981
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发表时间：
2016-01
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通讯作者：
Jan Vomacka;V. Korotkov;B. Bauer;Franziska Weinandy;Martin H. Kunzmann;J. Krysiak;Oliver Baron;T. Böttcher;K. Lorenz‐Baath;S. Sieber
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作者：
Jan Vomacka;V. Korotkov;B. Bauer;Franziska Weinandy;Martin H. Kunzmann;J. Krysiak;Oliver Baron;T. Böttcher;K. Lorenz‐Baath;S. Sieber
耐甲氧西林金黄色葡萄球菌（MRSA）导致严重感染，目前只有少数有效的抗生素治疗。为了应对这一挑战，迫切需要具有新颖且无抗性作用模式的化学实体。在这里，我们介绍了一种新的羟基酰胺化合物，有效地减少了破坏性毒素在各种S。金黄色葡萄球菌和MRSA菌株。通过转录组分析以及基于亲和力的蛋白质谱分析研究了分子机制。几个发病机制相关基因的下调表明抑制了中枢毒力相关途径。基于质谱的化学蛋白质组学揭示了推定的分子靶点。在MRSA小鼠皮肤感染模型中，用羟基酰胺进行的全身治疗显示脓肿大小显著减小。体外没有耐药性发展进一步强调了这一发现，即与直接解决细菌存活的抗生素相比，靶向毒力可能导致延长治疗选择。
Methicillin-resistant Staphylococcus aureus (MRSA) causes severe infections with only few effective antibiotic therapies currently available. To approach this challenge, chemical entities with a novel and resistance-free mode of action are desperately needed. Here, we introduce a new hydroxyamide compound that effectively reduces the expression of devastating toxins in various S. aureus and MRSA strains. The molecular mechanism was investigated by transcriptome analysis as well as by affinity-based protein profiling. Down-regulation of several pathogenesis associated genes suggested the inhibition of a central virulence-related pathway. Mass spectrometry-based chemical proteomics revealed putative molecular targets. Systemic treatment with the hydroxyamide showed significant reduction of abscess sizes in a MRSA mouse skin infection model. The absence of resistance development in vitro further underlines the finding that targeting virulence could lead to prolonged therapeutic options in comparison to antibiotics that directly address bacterial survival.