Comparison of proteomic responses as global approach to antibiotic mechanism of action elucidation

Christoph H.R. Senges, Jennifer J. Stepanek, Michaela Wenzel, Nadja Raatschen, Ümran Ay, Yvonne Märtens, Pascal Prochnow, Melissa Vázquez Hernández, Abdulkadir Yayci, Britta Schubert, Niklas B.M. Janzing, Helen L. Warmuth, Martin Kozik, Jens Bongard, John N. Alumasa, Bauke Albada, Maya Penkova, Tadeja Lukežič, Nohemy A. Sorto, Nicole LorenzReece G. Miller, Bingyao Zhu, Martin Benda, Jörg Stülke, Sina Schäkermann, Lars I. Leichert, Kathi Scheinpflug, Heike Brötz-Oesterhelt, Christian Hertweck, Jared T. Shaw, Hrvoje Petković, Jean M. Brunel, Kenneth C. Keiler, Nils Metzler-Nolte, Julia E. Bandow*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

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.

Original languageEnglish
Article numbere01373-20
JournalAntimicrobial Agents and Chemotherapy
Volume65
Issue number1
DOIs
Publication statusPublished - Jan 2021

Keywords

  • Antibiotic
  • Chemical biology
  • Mechanism of action
  • Physiology
  • Proteomics

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