TY - JOUR
T1 - Comparison of proteomic responses as global approach to antibiotic mechanism of action elucidation
AU - Senges, Christoph H.R.
AU - Stepanek, Jennifer J.
AU - Wenzel, Michaela
AU - Raatschen, Nadja
AU - Ay, Ümran
AU - Märtens, Yvonne
AU - Prochnow, Pascal
AU - Hernández, Melissa Vázquez
AU - Yayci, Abdulkadir
AU - Schubert, Britta
AU - Janzing, Niklas B.M.
AU - Warmuth, Helen L.
AU - Kozik, Martin
AU - Bongard, Jens
AU - Alumasa, John N.
AU - Albada, Bauke
AU - Penkova, Maya
AU - Lukežič, Tadeja
AU - Sorto, Nohemy A.
AU - Lorenz, Nicole
AU - Miller, Reece G.
AU - Zhu, Bingyao
AU - Benda, Martin
AU - Stülke, Jörg
AU - Schäkermann, Sina
AU - Leichert, Lars I.
AU - Scheinpflug, Kathi
AU - Brötz-Oesterhelt, Heike
AU - Hertweck, Christian
AU - Shaw, Jared T.
AU - Petković, Hrvoje
AU - Brunel, Jean M.
AU - Keiler, Kenneth C.
AU - Metzler-Nolte, Nils
AU - Bandow, Julia E.
N1 - Funding Information:
We thank Dickon Alley and Stephanie Grond for supplying compounds and RUBION for support. We gratefully acknowledge funding from the German Research Foundation (BA 4193/ 6-1); the German Federal State of North Rhine-Westphalia for the mass spectrometer (Forschungsgro?ger?te der L?nder); the National Institutes of Health (R01GM121650 to K.C.K. and NIAID/R01AI08093 to N.A.S. and J.T.S.); NRW grant Translation of Innovative Antibiotics to J.E.B. and N.M.-N.; the German Federal State of North Rhine-Westphalia and the European Union, European Regional Development Fund, Investing in Your Future (Innovative Antibiotics from the NRW to J.E.B., H.B.-O., and N.M.-N. and the Research Infrastructure Center for System-Based Antibiotic Research [CESAR] to J.E.B.); SPIRIT Slovenija (P-MR-09/104 to T.L.); and the Ministry of Higher Education, Science, and Technology (Slovenian Research Agency, ARRS, J4-8226 and P4-0116 to H.P.). C.H.R.S. and J.E.B. designed research and wrote the paper. J.J.S., M.W., N.R., ?.A., Y.M., P.P., M.V.H., A.Y., B.S., N.B.M.J., H.L.W., M.K., J.B., and J.E.B. collected data. C.H.R.S., J.J.S., M.W., N.R., and S.S. evaluated data. C.H.R.S. assembled the data. M.B. created mutants. B.Z. and J.S. integrated the data into SubtiWiki. J.N.A., B.A., M.P., T.L., N.A.S., N.L., and R.M. synthesized or purified compounds. L.I.L., K.S., H.B.-O., C.H., J.T.S., H.P., J.M.B., K.C.K., and N.M.-N. supplied substances. T.L. and H.P. worked at Acies Bio (Slovenia) at the time when the experiments were performed.
Funding Information:
We gratefully acknowledge funding from the German Research Foundation (BA 4193/ 6-1); the German Federal State of North Rhine-Westphalia for the mass spectrometer (Forschungsgroßgeräte der Länder); the National Institutes of Health (R01GM121650 to K.C.K. and NIAID/R01AI08093 to N.A.S. and J.T.S.); NRW grant Translation of Innovative Antibiotics to J.E.B. and N.M.-N.; the German Federal State of North Rhine-Westphalia and the European Union, European Regional Development Fund, Investing in Your Future (Innovative Antibiotics from the NRW to J.E.B., H.B.-O., and N.M.-N. and the Research Infrastructure Center for System-Based Antibiotic Research [CESAR] to J.E.B.); SPIRIT Slovenija (P-MR-09/104 to T.L.); and the Ministry of Higher Education, Science, and Technology (Slovenian Research Agency, ARRS, J4-8226 and P4-0116 to H.P.).
Publisher Copyright:
© 2020 Senges et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.
PY - 2021/1
Y1 - 2021/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85098653221&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85098653221&partnerID=8YFLogxK
U2 - 10.1128/AAC.01373-20
DO - 10.1128/AAC.01373-20
M3 - Article
C2 - 33046497
AN - SCOPUS:85098653221
SN - 0066-4804
VL - 65
JO - Antimicrobial agents and chemotherapy
JF - Antimicrobial agents and chemotherapy
IS - 1
M1 - e01373-20
ER -