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 Lorenz; Reece 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

doi:10.1128/AAC.01373-20

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 journal › Article › Academic › peer-review

33 Citations (Scopus)

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 language	English
Article number	e01373-20
Journal	Antimicrobial Agents and Chemotherapy
Volume	65
Issue number	1
DOIs	https://doi.org/10.1128/AAC.01373-20
Publication status	Published - Jan 2021
Externally published	Yes

Keywords

Antibiotic
Chemical biology
Mechanism of action
Physiology
Proteomics

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Senges, C. H. R., Stepanek, J. J., Wenzel, M., Raatschen, N., Ay, Ü., Märtens, Y., Prochnow, P., Hernández, M. V., Yayci, A., Schubert, B., Janzing, N. B. M., Warmuth, H. L., Kozik, M., Bongard, J., Alumasa, J. N., Albada, B., Penkova, M., Lukežič, T., Sorto, N. A., ... Bandow, J. E. (2021). Comparison of proteomic responses as global approach to antibiotic mechanism of action elucidation. Antimicrobial Agents and Chemotherapy, 65(1), Article e01373-20. https://doi.org/10.1128/AAC.01373-20

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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.",

keywords = "Antibiotic, Chemical biology, Mechanism of action, Physiology, Proteomics",

author = "Senges, {Christoph H.R.} and Stepanek, {Jennifer J.} and Michaela Wenzel and Nadja Raatschen and {\"U}mran Ay and Yvonne M{\"a}rtens and Pascal Prochnow and Hern{\'a}ndez, {Melissa V{\'a}zquez} and Abdulkadir Yayci and Britta Schubert and Janzing, {Niklas B.M.} and Warmuth, {Helen L.} and Martin Kozik and Jens Bongard and Alumasa, {John N.} and Bauke Albada and Maya Penkova and Tadeja Luke{\v z}i{\v c} and Sorto, {Nohemy A.} and Nicole Lorenz and Miller, {Reece G.} and Bingyao Zhu and Martin Benda and J{\"o}rg St{\"u}lke and Sina Sch{\"a}kermann and Leichert, {Lars I.} and Kathi Scheinpflug and Heike Br{\"o}tz-Oesterhelt and Christian Hertweck and Shaw, {Jared T.} and Hrvoje Petkovi{\'c} and Brunel, {Jean M.} and Keiler, {Kenneth C.} and Nils Metzler-Nolte and Bandow, {Julia E.}",

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month = jan,

doi = "10.1128/AAC.01373-20",

language = "English",

volume = "65",

journal = "Antimicrobial Agents and Chemotherapy",

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Senges, CHR, Stepanek, JJ, Wenzel, M, Raatschen, N, Ay, Ü, Märtens, Y, Prochnow, P, Hernández, MV, 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 2021, 'Comparison of proteomic responses as global approach to antibiotic mechanism of action elucidation', Antimicrobial Agents and Chemotherapy, vol. 65, no. 1, e01373-20. https://doi.org/10.1128/AAC.01373-20

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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.

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.

KW - Antibiotic

KW - Chemical biology

KW - Mechanism of action

KW - Physiology

KW - Proteomics

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 -

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

Abstract

Keywords

UN SDGs

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