Comparison of proteomic responses as global approach to antibiotic mechanism of action elucidation
Journal article, 2021
This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license. 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.
Physiology
Antibiotic
Chemical biology
Mechanism of action
Proteomics
Author
Christoph H.R. Senges
Ruhr-Universität Bochum
Jennifer J. Stepanek
Ruhr-Universität Bochum
Michaela Wenzel
Chalmers, Biology and Biological Engineering, Chemical Biology
Ruhr-Universität Bochum
Nadja Raatschen
Ruhr-Universität Bochum
Ümran Ay
Ruhr-Universität Bochum
Yvonne Märtens
Ruhr-Universität Bochum
Pascal Prochnow
Ruhr-Universität Bochum
Melissa Vázquez Hernández
Ruhr-Universität Bochum
Abdulkadir Yayci
Ruhr-Universität Bochum
Britta Schubert
Ruhr-Universität Bochum
Niklas B.M. Janzing
Ruhr-Universität Bochum
Helen L. Warmuth
Ruhr-Universität Bochum
Martin Kozik
Ruhr-Universität Bochum
Jens Bongard
Ruhr-Universität Bochum
John N. Alumasa
Pennsylvania State University
Bauke Albada
Wageningen University and Research
Ruhr-Universität Bochum
Maya Penkova
Ruhr-Universität Bochum
Tadeja Lukežič
Acies Bio D.O.O.
National Institute of Biology Ljubljana
Nohemy A. Sorto
University of California
Nicole Lorenz
Ruhr-Universität Bochum
Reece G. Miller
Ruhr-Universität Bochum
Bingyao Zhu
University of Göttingen
Martin Benda
University of Göttingen
J. Stülke
University of Göttingen
Sina Schäkermann
Ruhr-Universität Bochum
Lars I. Leichert
Ruhr-Universität Bochum
Kathi Scheinpflug
Leibniz-Institut für Zoo- und Wildtierforschung
Leibniz-Institut für Molekulare Pharmakologie
Heike Brötz-Oesterhelt
University of Tübingen
C. Hertweck
Hans-Knoll-Institute (HKI)
Jared T. Shaw
University of California
Hrvoje Petković
University of Ljubljana
Jean M. Brunel
Transporteurs Membranaires, Chimiorésistance et Drug-Design
Kenneth C. Keiler
Pennsylvania State University
Nils Metzler-Nolte
Ruhr-Universität Bochum
Julia E. Bandow
Ruhr-Universität Bochum
Antimicrobial Agents and Chemotherapy
0066-4804 (ISSN) 1098-6596 (eISSN)
Vol. 65 1 e01373-20Subject Categories
Microbiology in the medical area
DOI
10.1128/AAC.01373-20
PubMed
33046497