Mechanistic insights into the C55-P targeting lipopeptide antibiotics revealed by structure–activity studies and high-resolution crystal structures†

Thomas M. Wood; Matthieu R. Zeronian; Ned Buijs; Kristine Bertheussen; Hanieh K. Abedian; Aidan V. Johnson; Nicholas M. Pearce; Martin Lutz; Johan Kemmink; Tjalling Seirsma; Leendert W. Hamoen; Bert J. C. Janssen; Nathaniel I. Martin

doi:10.1039/d1sc07190d

Mechanistic insights into the C55-P targeting lipopeptide antibiotics revealed by structure–activity studies and high-resolution crystal structures†

Thomas M. Wood, Matthieu R. Zeronian, Ned Buijs, Kristine Bertheussen, Hanieh K. Abedian, Aidan V. Johnson, Nicholas M. Pearce, Martin Lutz, Johan Kemmink, Tjalling Seirsma, Leendert W. Hamoen, Bert J. C. Janssen, Nathaniel I. Martin

Biological Chemistry Group, Institute of Biology Leiden, Leiden University, Sylviusweg 72, 2333 BE Leiden, The Netherlands
Bacterial Cell Biology and Physiology Group, Swammerdam Institute for Life Sciences, University of Amsterdam, Science Park 904, 1098 XH Amsterdam, The Netherlands
Faculty of Science and Engineering, University of Groningen, 9747 AG Groningen, The Netherlands
Utrecht University
Department of Chemical Biology & Drug Discovery, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Universiteitsweg 99, 3584 CG Utrecht, The Netherlands. [email protected].

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

The continued rise of antibiotic resistance is a global concern that threatens to undermine many aspects of modern medical practice. Key to addressing this threat is the discovery and development of new antibiotics that operate by unexploited modes of action. The so-called calcium-dependent lipopeptide antibiotics (CDAs) are an important emerging class of natural products that provides a source of new antibiotic agents rich in structural and mechanistic diversity. Notable in this regard is the subset of CDAs comprising the laspartomycins and amphomycins/friulimicins that specifically target the bacterial cell wall precursor undecaprenyl phosphate (C55-P). In this study we describe the design and synthesis of new C55-P-targeting CDAs with structural features drawn from both the laspartomycin and amphomycin/friulimicin classes. Assessment of these lipopeptides revealed previously unknown and surprisingly subtle structural features that are required for antibacterial activity. High-resolution crystal structures further indicate that the amphomycin/friulimicin-like lipopeptides adopt a unique crystal packing that governs their interaction with C55-P and provides an explanation for their antibacterial effect. In addition, live-cell microscopy studies provide further insights into the biological activity of the C55-P targeting CDAs highlighting their unique mechanism of action relative to the clinically used CDA daptomycin.

Original language	English
Pages (from-to)	2985-2991
Number of pages	7
Journal	Chemical Science
Volume	13
Issue number	10
DOIs	https://doi.org/10.1039/d1sc07190d
Publication status	Published - 21 Feb 2022

Bibliographical note

Funding Information:
Financial support provided by the Netherlands Organization for Scientific Research (NWO PhD grant to T. M. W.) and the European Research Council (ERC consolidator grant to N. I. M., grant agreement no. 725523, and ERC starting grant to B. J. C. J., grant agreement no. 677500). We thank Paolo Innocenti for performing HRMS analyses and Fons Lefeber for assistance in acquiring NMR spectra. Professor Tanja Schneider is kindly thanked for providing an authentic sample of friulimicin B. We thank the staff at beamlines I04-1 and I04 of the Diamond Light Source (Harwell, United Kingdom) for diffraction data collection.

Publisher Copyright:
© 2022 Royal Society of Chemistry. All rights reserved.

Access to Document

10.1039/d1sc07190dLicence: CC BY-NC

d1sc07190dFinal published version, 2.04 MBLicence: CC BY-NC

http://xlink.rsc.org/?DOI=D1SC07190D

Cite this

Wood, T. M., Zeronian, M. R., Buijs, N., Bertheussen, K., Abedian, H. K., Johnson, A. V., Pearce, N. M., Lutz, M., Kemmink, J., Seirsma, T., Hamoen, L. W., Janssen, B. J. C., & Martin, N. I. (2022). Mechanistic insights into the C55-P targeting lipopeptide antibiotics revealed by structure–activity studies and high-resolution crystal structures†. Chemical Science, 13(10), 2985-2991. https://doi.org/10.1039/d1sc07190d

@article{c8de8682de6c4f3ca0bcc250a06e9f21,

title = "Mechanistic insights into the C55-P targeting lipopeptide antibiotics revealed by structure–activity studies and high-resolution crystal structures†",

abstract = "The continued rise of antibiotic resistance is a global concern that threatens to undermine many aspects of modern medical practice. Key to addressing this threat is the discovery and development of new antibiotics that operate by unexploited modes of action. The so-called calcium-dependent lipopeptide antibiotics (CDAs) are an important emerging class of natural products that provides a source of new antibiotic agents rich in structural and mechanistic diversity. Notable in this regard is the subset of CDAs comprising the laspartomycins and amphomycins/friulimicins that specifically target the bacterial cell wall precursor undecaprenyl phosphate (C55-P). In this study we describe the design and synthesis of new C55-P-targeting CDAs with structural features drawn from both the laspartomycin and amphomycin/friulimicin classes. Assessment of these lipopeptides revealed previously unknown and surprisingly subtle structural features that are required for antibacterial activity. High-resolution crystal structures further indicate that the amphomycin/friulimicin-like lipopeptides adopt a unique crystal packing that governs their interaction with C55-P and provides an explanation for their antibacterial effect. In addition, live-cell microscopy studies provide further insights into the biological activity of the C55-P targeting CDAs highlighting their unique mechanism of action relative to the clinically used CDA daptomycin.",

author = "Wood, {Thomas M.} and Zeronian, {Matthieu R.} and Ned Buijs and Kristine Bertheussen and Abedian, {Hanieh K.} and Johnson, {Aidan V.} and Pearce, {Nicholas M.} and Martin Lutz and Johan Kemmink and Tjalling Seirsma and Hamoen, {Leendert W.} and Janssen, {Bert J. C.} and Martin, {Nathaniel I.}",

note = "Funding Information: Financial support provided by the Netherlands Organization for Scientific Research (NWO PhD grant to T. M. W.) and the European Research Council (ERC consolidator grant to N. I. M., grant agreement no. 725523, and ERC starting grant to B. J. C. J., grant agreement no. 677500). We thank Paolo Innocenti for performing HRMS analyses and Fons Lefeber for assistance in acquiring NMR spectra. Professor Tanja Schneider is kindly thanked for providing an authentic sample of friulimicin B. We thank the staff at beamlines I04-1 and I04 of the Diamond Light Source (Harwell, United Kingdom) for diffraction data collection. Publisher Copyright: {\textcopyright} 2022 Royal Society of Chemistry. All rights reserved.",

year = "2022",

month = feb,

day = "21",

doi = "10.1039/d1sc07190d",

language = "English",

volume = "13",

pages = "2985--2991",

journal = "Chemical Science",

issn = "2041-6520",

publisher = "Royal Society of Chemistry",

number = "10",

}

Wood, TM, Zeronian, MR, Buijs, N, Bertheussen, K, Abedian, HK, Johnson, AV, Pearce, NM, Lutz, M, Kemmink, J, Seirsma, T, Hamoen, LW, Janssen, BJC & Martin, NI 2022, 'Mechanistic insights into the C55-P targeting lipopeptide antibiotics revealed by structure–activity studies and high-resolution crystal structures†', Chemical Science, vol. 13, no. 10, pp. 2985-2991. https://doi.org/10.1039/d1sc07190d

TY - JOUR

T1 - Mechanistic insights into the C55-P targeting lipopeptide antibiotics revealed by structure–activity studies and high-resolution crystal structures†

AU - Wood, Thomas M.

AU - Zeronian, Matthieu R.

AU - Buijs, Ned

AU - Bertheussen, Kristine

AU - Abedian, Hanieh K.

AU - Johnson, Aidan V.

AU - Pearce, Nicholas M.

AU - Lutz, Martin

AU - Kemmink, Johan

AU - Seirsma, Tjalling

AU - Hamoen, Leendert W.

AU - Janssen, Bert J. C.

AU - Martin, Nathaniel I.

N1 - Funding Information: Financial support provided by the Netherlands Organization for Scientific Research (NWO PhD grant to T. M. W.) and the European Research Council (ERC consolidator grant to N. I. M., grant agreement no. 725523, and ERC starting grant to B. J. C. J., grant agreement no. 677500). We thank Paolo Innocenti for performing HRMS analyses and Fons Lefeber for assistance in acquiring NMR spectra. Professor Tanja Schneider is kindly thanked for providing an authentic sample of friulimicin B. We thank the staff at beamlines I04-1 and I04 of the Diamond Light Source (Harwell, United Kingdom) for diffraction data collection. Publisher Copyright: © 2022 Royal Society of Chemistry. All rights reserved.

PY - 2022/2/21

Y1 - 2022/2/21

N2 - The continued rise of antibiotic resistance is a global concern that threatens to undermine many aspects of modern medical practice. Key to addressing this threat is the discovery and development of new antibiotics that operate by unexploited modes of action. The so-called calcium-dependent lipopeptide antibiotics (CDAs) are an important emerging class of natural products that provides a source of new antibiotic agents rich in structural and mechanistic diversity. Notable in this regard is the subset of CDAs comprising the laspartomycins and amphomycins/friulimicins that specifically target the bacterial cell wall precursor undecaprenyl phosphate (C55-P). In this study we describe the design and synthesis of new C55-P-targeting CDAs with structural features drawn from both the laspartomycin and amphomycin/friulimicin classes. Assessment of these lipopeptides revealed previously unknown and surprisingly subtle structural features that are required for antibacterial activity. High-resolution crystal structures further indicate that the amphomycin/friulimicin-like lipopeptides adopt a unique crystal packing that governs their interaction with C55-P and provides an explanation for their antibacterial effect. In addition, live-cell microscopy studies provide further insights into the biological activity of the C55-P targeting CDAs highlighting their unique mechanism of action relative to the clinically used CDA daptomycin.

AB - The continued rise of antibiotic resistance is a global concern that threatens to undermine many aspects of modern medical practice. Key to addressing this threat is the discovery and development of new antibiotics that operate by unexploited modes of action. The so-called calcium-dependent lipopeptide antibiotics (CDAs) are an important emerging class of natural products that provides a source of new antibiotic agents rich in structural and mechanistic diversity. Notable in this regard is the subset of CDAs comprising the laspartomycins and amphomycins/friulimicins that specifically target the bacterial cell wall precursor undecaprenyl phosphate (C55-P). In this study we describe the design and synthesis of new C55-P-targeting CDAs with structural features drawn from both the laspartomycin and amphomycin/friulimicin classes. Assessment of these lipopeptides revealed previously unknown and surprisingly subtle structural features that are required for antibacterial activity. High-resolution crystal structures further indicate that the amphomycin/friulimicin-like lipopeptides adopt a unique crystal packing that governs their interaction with C55-P and provides an explanation for their antibacterial effect. In addition, live-cell microscopy studies provide further insights into the biological activity of the C55-P targeting CDAs highlighting their unique mechanism of action relative to the clinically used CDA daptomycin.

UR - http://www.scopus.com/inward/record.url?scp=85127206719&partnerID=8YFLogxK

U2 - 10.1039/d1sc07190d

DO - 10.1039/d1sc07190d

M3 - Article

C2 - 35382464

SN - 2041-6520

VL - 13

SP - 2985

EP - 2991

JO - Chemical Science

JF - Chemical Science

IS - 10

ER -

Mechanistic insights into the C55-P targeting lipopeptide antibiotics revealed by structure–activity studies and high-resolution crystal structures†

Abstract

Bibliographical note

Access to Document

Other files and links

Fingerprint

Cite this