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 e01373-20

Subject Categories

Microbiology in the medical area

DOI

10.1128/AAC.01373-20

PubMed

33046497

More information

Latest update

1/14/2021