Comparison of Proteomic Responses as Global Approach to Antibiotic Mechanism of Action Elucidation.
Comparison of Proteomic Responses as Global Approach to Antibiotic Mechanism of Action Elucidation.
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DOI：
10.1128/aac.01373-20
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发表时间：
2020-12-16
影响因子：
4.9
通讯作者：
Bandow JE
中科院分区：
文献类型：
--
作者：
Senges CHR;Stepanek JJ;Wenzel M;Raatschen N;Ay Ü;Märtens Y;Prochnow P;Vázquez Hernández M;Yayci A;Schubert B;Janzing NBM;Warmuth HL;Kozik M;Bongard J;Alumasa JN;Albada B;Penkova M;Lukežič T;Sorto NA;Lorenz N;Miller RG;Zhu B;Benda M;Stülke J;Schäkermann S;Leichert LI;Scheinpflug K;Brötz-Oesterhelt H;Hertweck C;Shaw JT;Petković H;Brunel JM;Keiler KC;Metzler-Nolte N;Bandow JE
迫切需要新的抗生素来应对日益严重的耐药性挑战。在早期药物发现中，瓶颈之一是靶点和机制的阐明。为了加速抗生素研究，我们提供了一种蛋白质组学方法，用于将化合物快速分类为具有先例和前所未有的作用模式的化合物。我们建立了一个涵盖91种抗生素和比较化合物的枯草芽孢杆菌蛋白质组反应文库，并开发了一种数学方法来辅助数据分析。迫切需要新的抗生素来应对日益严重的耐药性挑战。在早期药物发现中，瓶颈之一是靶点和机制的阐明。为了加速抗生素研究，我们提供了一种蛋白质组学方法，用于将化合物快速分类为具有先例和前所未有的作用模式的化合物。我们建立了一个涵盖91种抗生素和比较化合物的枯草芽孢杆菌蛋白质组反应文库，并开发了一种数学方法来辅助数据分析。蛋白质组学反应（CoPR）的比较允许快速鉴定具有双重作用机制的抗生素，如非典型四环素所示。它还有助于产生关于salvarsan（arsphenamine）和抗风湿药金诺芬（auranofin）作用机制的假设，金诺芬正在考虑重新利用。蛋白质组学分析还通过分析指示细胞过程和结构受损的标记蛋白来深入了解抗生素对细菌生理学的影响。如反式翻译所证明的，一个有前途的目标尚未在临床上开发，蛋白质组学分析支持化学生物学方法来研究细菌生理学。
New antibiotics are urgently needed to address the mounting resistance challenge. In early drug discovery, one of the bottlenecks is the elucidation of targets and mechanisms. To accelerate antibiotic research, we provide a proteomic approach for the rapid classification of compounds into those with precedented and unprecedented modes of action. We established a proteomic response library of Bacillus subtilis covering 91 antibiotics and comparator compounds, and a mathematical approach was developed to aid data analysis. New antibiotics are urgently needed to address the mounting resistance challenge. In early drug discovery, one of the bottlenecks is the elucidation of targets and mechanisms. To accelerate antibiotic research, we provide a proteomic approach for the rapid classification of compounds into those with precedented and unprecedented modes of action. We established a proteomic response library of Bacillus subtilis covering 91 antibiotics and comparator compounds, and a mathematical approach was developed to aid data analysis. Comparison of proteomic responses (CoPR) allows the rapid identification of antibiotics with dual mechanisms of action as shown for atypical tetracyclines. It also aids in generating hypotheses on mechanisms of action as presented for salvarsan (arsphenamine) and the antirheumatic agent auranofin, which is under consideration for repurposing. Proteomic profiling also provides insights into the impact of antibiotics on bacterial physiology through analysis of marker proteins indicative of the impairment of cellular processes and structures. As demonstrated for trans-translation, a promising target not yet exploited clinically, proteomic profiling supports chemical biology approaches to investigating bacterial physiology.