ACS Publications. Most Trusted. Most Cited. Most Read
My Activity
CONTENT TYPES

Using Nanoscopy To Probe the Biological Activity of Antimicrobial Leads That Display Potent Activity against Pathogenic, Multidrug Resistant, Gram-Negative Bacteria

  • Kirsty L. Smitten
    Kirsty L. Smitten
    Department of Chemistry, The University of Sheffield, Western Bank, Sheffield S3 7HF, U.K.
  • Hannah M. Southam*
    Hannah M. Southam
    Department of Molecular Biology and Biotechnology, The University of Sheffield, Western Bank, Sheffield S10 2TN, U.K.
    *E-mail: [email protected]
  • Jorge Bernardino de la Serna
    Jorge Bernardino de la Serna
    Central Laser Facility, Rutherford Appleton Laboratory, Research Complex at Harwell, Science and Technology Facilities Council, Harwell-Oxford, Didcot OX11 0QX, U.K.
    Department of Physics, King’s College London, London WC2R 2LS, U.K.
  • Martin R. Gill
    Martin R. Gill
    Department of Chemistry, The University of Sheffield, Western Bank, Sheffield S3 7HF, U.K.
  • Paul J. Jarman
    Paul J. Jarman
    Department of Biomedical Science, The University of Sheffield, Western Bank, Sheffield S10 2TN, U.K.
  • Carl G. W. Smythe
    Carl G. W. Smythe
    Department of Biomedical Science, The University of Sheffield, Western Bank, Sheffield S10 2TN, U.K.
  • Robert K. Poole*
    Robert K. Poole
    Department of Molecular Biology and Biotechnology, The University of Sheffield, Western Bank, Sheffield S10 2TN, U.K.
    *E-mail: [email protected]
  • , and 
  • Jim A. Thomas*
    Jim A. Thomas
    Department of Chemistry, The University of Sheffield, Western Bank, Sheffield S3 7HF, U.K.
    *E-mail: [email protected]
Cite this: ACS Nano 2019, 13, 5, 5133–5146
Publication Date (Web):April 9, 2019
https://doi.org/10.1021/acsnano.8b08440
Copyright © 2019 American Chemical Society

    Article Views

    4384

    Altmetric

    -

    Citations

    LEARN ABOUT THESE METRICS
    Other access options
    Supporting Info (1)»

    Abstract

    Abstract Image

    Medicinal leads that are also compatible with imaging technologies are attractive, as they facilitate the development of therapeutics through direct mechanistic observations at the molecular level. In this context, the uptake and antimicrobial activities of several luminescent dinuclear RuII complexes against E. coli were assessed and compared to results obtained for another ESKAPE pathogen, the Gram-positive major opportunistic pathogen Enterococcus faecalis, V583. The most promising lead displays potent activity, particularly against the Gram-negative bacteria, and potency is retained in the uropathogenic multidrug resistant EC958 ST131 strain. Exploiting the inherent luminescent properties of this complex, super-resolution STED nanoscopy was used to image its initial localization at/in cellular membranes and its subsequent transfer to the cell poles. Membrane damage assays confirm that the complex disrupts the bacterial membrane structure before internalization. Mammalian cell culture and animal model studies indicate that the complex is not toxic to eukaryotes, even at concentrations that are several orders of magnitude higher than its minimum inhibitory concentration (MIC). Taken together, these results have identified a lead molecular architecture for hard-to-treat, multiresistant, Gram-negative bacteria, which displays activities that are already comparable to optimized natural product-based leads.

    Read this article

    To access this article, please review the available access options below.

    Get instant access

    Purchase Access

    Read this article for 48 hours. Check out below using your ACS ID or as a guest.

    Recommended

    Access through Your Institution

    You may have access to this article through your institution.

    Your institution does not have access to this content. You can change your affiliated institution below.

    Supporting Information

    ARTICLE SECTIONS
    Jump To

    The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsnano.8b08440.

    • Supplementary Data; Instrumentation (PDF)

    Terms & Conditions

    Most electronic Supporting Information files are available without a subscription to ACS Web Editions. Such files may be downloaded by article for research use (if there is a public use license linked to the relevant article, that license may permit other uses). Permission may be obtained from ACS for other uses through requests via the RightsLink permission system: http://pubs.acs.org/page/copyright/permissions.html.

    Cited By

    This article is cited by 49 publications.

    1. Angelo Frei, Alysha G. Elliott, Alex Kan, Hue Dinh, Stefan Bräse, Alice E. Bruce, Mitchell R. Bruce, Feng Chen, Dhirgam Humaidy, Nicole Jung, A. Paden King, Peter G. Lye, Hanna K. Maliszewska, Ahmed M. Mansour, Dimitris Matiadis, María Paz Muñoz, Tsung-Yu Pai, Shyam Pokhrel, Peter J. Sadler, Marina Sagnou, Michelle Taylor, Justin J. Wilson, Dean Woods, Johannes Zuegg, Wieland Meyer, Amy K. Cain, Matthew A. Cooper, Mark A. T. Blaskovich. Metal Complexes as Antifungals? From a Crowd-Sourced Compound Library to the First In Vivo Experiments. JACS Au 2022, 2 (10) , 2277-2294. https://doi.org/10.1021/jacsau.2c00308
    2. Fabian Dröge, Felicity F. Noakes, Stuart A. Archer, Sreejesh Sreedharan, Ahtasham Raza, Craig C. Robertson, Sheila MacNeil, John W. Haycock, Heather Carson, Anthony J. H. M. Meijer, Carl G. W. Smythe, Jorge Bernardino de la Serna, Benjamin Dietzek-Ivanšić, Jim A. Thomas. A Dinuclear Osmium(II) Complex Near-Infrared Nanoscopy Probe for Nuclear DNA. Journal of the American Chemical Society 2021, 143 (48) , 20442-20453. https://doi.org/10.1021/jacs.1c10325
    3. Frederico A. Baptista, Dorottya Krizsan, Mark Stitch, Igor V. Sazanovich, Ian P. Clark, Michael Towrie, Conor Long, Lara Martinez-Fernandez, Roberto Improta, Noel A. P. Kane-Maguire, John M. Kelly, Susan J. Quinn. Adenine Radical Cation Formation by a Ligand-Centered Excited State of an Intercalated Chromium Polypyridyl Complex Leads to Enhanced DNA Photo-oxidation. Journal of the American Chemical Society 2021, 143 (36) , 14766-14779. https://doi.org/10.1021/jacs.1c06658
    4. Adam M. Varney, Kirsty L. Smitten, Jim A. Thomas, Samantha McLean. Transcriptomic Analysis of the Activity and Mechanism of Action of a Ruthenium(II)-Based Antimicrobial That Induces Minimal Evolution of Pathogen Resistance. ACS Pharmacology & Translational Science 2021, 4 (1) , 168-178. https://doi.org/10.1021/acsptsci.0c00159
    5. Anupam Roy, Suneel Kumar Srivastava, Shanker Lal Shrivastava, Amit Kumar Mandal. Hierarchical Assembly of Nanodimensional Silver–Silver Oxide Physical Gels Controlling Nosocomial Infections. ACS Omega 2020, 5 (50) , 32617-32631. https://doi.org/10.1021/acsomega.0c04957
    6. Ajay Gupta, Puja Prasad, Shalini Gupta, Pijus K. Sasmal. Simultaneous Ultrasensitive Detection and Elimination of Drug-Resistant Bacteria by Cyclometalated Iridium(III) Complexes. ACS Applied Materials & Interfaces 2020, 12 (32) , 35967-35976. https://doi.org/10.1021/acsami.0c11161
    7. Ruma Ghosh, Mehak Malhotra, Rupali Ravindra Madhuri Sathe, Manickam Jayakannan. Biodegradable Polymer Theranostic Fluorescent Nanoprobe for Direct Visualization and Quantitative Determination of Antimicrobial Activity. Biomacromolecules 2020, 21 (7) , 2896-2912. https://doi.org/10.1021/acs.biomac.0c00653
    8. Wei Deng, Chun-Yan Zhang, Li-Xin Dou, Li-Ting Huang, Jin-Tiao Wang, Xiang-Wen Liao, Li-Ping Wang, Ru-Jian Yu, Yan-Shi Xiong. Polypyridyl ruthenium complexes with benzothiazole moiety as membrane disruptors and anti-resistance agents for Staphylococcus aureus. Journal of Inorganic Biochemistry 2024, 254 , 112517. https://doi.org/10.1016/j.jinorgbio.2024.112517
    9. Bishnu Das, Parna Gupta. Multimetallic transition metal complexes:Luminescent probes for biomolecule sensing, ion detection, imaging and therapeutic application. Coordination Chemistry Reviews 2024, 504 , 215656. https://doi.org/10.1016/j.ccr.2024.215656
    10. Tayler D. Prieto Otoya, Kane T. McQuaid, Joseph Hennessy, Georgia Menounou, Alex Gibney, Neil G. Paterson, David J. Cardin, Andrew Kellett, Christine J. Cardin. Probing a Major DNA Weakness: Resolving the Groove and Sequence Selectivity of the Diimine Complex Λ‐[Ru(phen) 2 phi] 2+. Angewandte Chemie International Edition 2024, 63 (13) https://doi.org/10.1002/anie.202318863
    11. Tayler D. Prieto Otoya, Kane T. McQuaid, Joseph Hennessy, Georgia Menounou, Alex Gibney, Neil G. Paterson, David J. Cardin, Andrew Kellett, Christine J. Cardin. Probing a Major DNA Weakness: Resolving the Groove and Sequence Selectivity of the Diimine Complex Λ‐[Ru(phen) 2 phi] 2+. Angewandte Chemie 2024, 136 (13) https://doi.org/10.1002/ange.202318863
    12. Mirco Scaccaglia, Michael P. Birbaumer, Silvana Pinelli, Giorgio Pelosi, Angelo Frei. Discovery of antibacterial manganese( i ) tricarbonyl complexes through combinatorial chemistry. Chemical Science 2024, 15 (11) , 3907-3919. https://doi.org/10.1039/D3SC05326A
    13. Markus Orsi, Boon Shing Loh, Cheng Weng, Wee Han Ang, Angelo Frei. Using Machine Learning to Predict the Antibacterial Activity of Ruthenium Complexes**. Angewandte Chemie International Edition 2024, 63 (10) https://doi.org/10.1002/anie.202317901
    14. Markus Orsi, Boon Shing Loh, Cheng Weng, Wee Han Ang, Angelo Frei. Maschinelles Lernen zur Vorhersage antibakterieller Aktivität von Ruthenium‐Komplexen**. Angewandte Chemie 2024, 136 (10) https://doi.org/10.1002/ange.202317901
    15. Sandra A. Bright, MariaLuisa Erby, Fergus E. Poynton, Daniel Monteyne, David Pérez-Morga, Thorfinnur Gunnlaugsson, D. Clive Williams, Robert B. P. Elmes. Tracking the cellular uptake and phototoxicity of Ru( ii )-polypyridyl-1,8-naphthalimide Tröger's base conjugates. RSC Chemical Biology 2024, 46 https://doi.org/10.1039/D3CB00206C
    16. Quentin Bugnon, Camilo Melendez, Oksana Desiatkina, Louis Fayolles de Chaptes, Isabelle Holzer, Emilia Păunescu, Markus Hilty, Julien Furrer, . In vitro antibacterial activity of dinuclear thiolato-bridged ruthenium(II)-arene compounds. Microbiology Spectrum 2023, 11 (6) https://doi.org/10.1128/spectrum.00954-23
    17. Annick van Niekerk, M. Cassiem Joseph, Angela Kavanagh, Hue Dinh, Andrew J. Swarts, Selwyn F. Mapolie, Johannes Zuegg, Amy K. Cain, Alysha G. Elliott, Mark A. T. Blaskovich, Angelo Frei. The Antimicrobial Properties of Pd II − and Ru II −pyta Complexes**. ChemBioChem 2023, 24 (19) https://doi.org/10.1002/cbic.202300247
    18. Xia Shan, Haojie Xie, Tianci Zhou, Meisheng Wu, Jie Yang. Dual DNA recycling amplifications coupled with Au NPs@ZIF-MOF accelerator for enhanced electrochemical ratiometric sensing of pathogenic bacteria. Talanta 2023, 263 , 124751. https://doi.org/10.1016/j.talanta.2023.124751
    19. Shuyi Lv, Chao Wang, Ke Xue, Jiaxin Wang, Minghui Xiao, Zhencheng Sun, Lei Han, Linqi Shi, Chunlei Zhu. Activated alkyne-enabled turn-on click bioconjugation with cascade signal amplification for ultrafast and high-throughput antibiotic screening. Proceedings of the National Academy of Sciences 2023, 120 (27) https://doi.org/10.1073/pnas.2302367120
    20. Angelo Frei, Anthony D. Verderosa, Alysha G. Elliott, Johannes Zuegg, Mark A. T. Blaskovich. Metals to combat antimicrobial resistance. Nature Reviews Chemistry 2023, 7 (3) , 202-224. https://doi.org/10.1038/s41570-023-00463-4
    21. Kirsty Smitten, Hannah M Southam, Simon Fairbanks, Arthur Graf, Adrien Chauvet, Jim A Thomas. Clearing an ESKAPE Pathogen in a Model Organism; A Polypyridyl Ruthenium(II) Complex Theranostic that Treats a Resistant Acinetobacter baumannii Infection in Galleria mellonella. Chemistry – A European Journal 2023, 29 (11) https://doi.org/10.1002/chem.202203555
    22. Isabelle I. Niyonshuti, Ariel Rogers, Deborah Okyere, Yong Wang, Jingyi Chen. Engineering silver nanoparticle surfaces for antimicrobial applications. 2023, 435-449. https://doi.org/10.1016/B978-0-12-822425-0.00099-3
    23. Saul M. Cooper, Christina Siakalli, Andrew J. P. White, Angelo Frei, Philip W. Miller, Nicholas J. Long. Synthesis and anti-microbial activity of a new series of bis(diphosphine) rhenium( v ) dioxo complexes. Dalton Transactions 2022, 51 (34) , 12791-12795. https://doi.org/10.1039/D2DT02157A
    24. Martin R. Gill, Paul J. Jarman, Vanessa Hearnden, Simon D Fairbanks, Marcella Bassetto, Hannes Maib, John Palmer, Kathryn R. Ayscough, Jim A. Thomas, Carl Smythe. A Ruthenium(II) Polypyridyl Complex Disrupts Actin Cytoskeleton Assembly and Blocks Cytokinesis. Angewandte Chemie 2022, 134 (27) https://doi.org/10.1002/ange.202117449
    25. Martin R. Gill, Paul J. Jarman, Vanessa Hearnden, Simon D Fairbanks, Marcella Bassetto, Hannes Maib, John Palmer, Kathryn R. Ayscough, Jim A. Thomas, Carl Smythe. A Ruthenium(II) Polypyridyl Complex Disrupts Actin Cytoskeleton Assembly and Blocks Cytokinesis. Angewandte Chemie International Edition 2022, 61 (27) https://doi.org/10.1002/anie.202117449
    26. Kenneth P. H. Pritzker, Andrea R. Pritzker. Fine Wine and Gout. Rheumato 2022, 2 (2) , 46-51. https://doi.org/10.3390/rheumato2020006
    27. Zhiyuan Gao, Dan Ding. AIE bio-conjugates for biomedical applications. 2022, 529-553. https://doi.org/10.1016/B978-0-12-824335-0.00009-X
    28. Po‐Yu Ho, Sin‐Ying Lee, Chuen Kam, Junfei Zhu, Guo‐Gang Shan, Yuning Hong, Wai‐Yeung Wong, Sijie Chen. Fluorescence Imaging and Photodynamic Inactivation of Bacteria Based on Cationic Cyclometalated Iridium(III) Complexes with Aggregation‐Induced Emission Properties. Advanced Healthcare Materials 2021, 10 (24) https://doi.org/10.1002/adhm.202100706
    29. Angelo Frei, Soumya Ramu, Gabrielle J. Lowe, Hue Dinh, Lucie Semenec, Alysha G. Elliott, Johannes Zuegg, Anke Deckers, Nicole Jung, Stefan Bräse, Amy K. Cain, Mark A. T. Blaskovich. Platinum Cyclooctadiene Complexes with Activity against Gram‐positive Bacteria. ChemMedChem 2021, 16 (20) , 3165-3171. https://doi.org/10.1002/cmdc.202100157
    30. Matthew D. Newton, Simon D. Fairbanks, Jim A. Thomas, David S. Rueda. A Minimal Load‐and‐Lock Ru II Luminescent DNA Probe. Angewandte Chemie International Edition 2021, 60 (38) , 20952-20959. https://doi.org/10.1002/anie.202108077
    31. Matthew D. Newton, Simon D. Fairbanks, Jim A. Thomas, David S. Rueda. A Minimal Load‐and‐Lock Ru II Luminescent DNA Probe. Angewandte Chemie 2021, 133 (38) , 21120-21127. https://doi.org/10.1002/ange.202108077
    32. Alexandra-Cristina Munteanu, Valentina Uivarosi. Ruthenium Complexes in the Fight against Pathogenic Microorganisms. An Extensive Review. Pharmaceutics 2021, 13 (6) , 874. https://doi.org/10.3390/pharmaceutics13060874
    33. Poppy J Hesketh-Best, Michelle V Mouritzen, Kayleigh Shandley-Edwards, Richard A Billington, Mathew Upton. Galleria mellonella larvae exhibit a weight-dependent lethal median dose when infected with methicillin-resistant Staphylococcus aureus. Pathogens and Disease 2021, 79 (2) https://doi.org/10.1093/femspd/ftab003
    34. Matthew Allison, Pablo Caramés‐Méndez, Christopher M. Pask, Roger M. Phillips, Rianne M. Lord, Patrick C. McGowan. Bis(bipyridine)ruthenium(II) Ferrocenyl β‐Diketonate Complexes: Exhibiting Nanomolar Potency against Human Cancer Cell Lines. Chemistry – A European Journal 2021, 27 (11) , 3737-3744. https://doi.org/10.1002/chem.202004024
    35. Hualong Song, Miles Postings, Peter Scott, Nicola J. Rogers. Metallohelices emulate the properties of short cationic α-helical peptides. Chemical Science 2021, 12 (5) , 1620-1631. https://doi.org/10.1039/D0SC06412B
    36. M.L. MARTIN‐FERNANDEZ. A brief history of the octopus imaging facility to celebrate its 10th anniversary. Journal of Microscopy 2021, 281 (1) , 3-15. https://doi.org/10.1111/jmi.12974
    37. Sara Nasiri Sovari, Sandra Vojnovic, Sanja Skaro Bogojevic, Aurelien Crochet, Aleksandar Pavic, Jasmina Nikodinovic-Runic, Fabio Zobi. Design, synthesis and in vivo evaluation of 3-arylcoumarin derivatives of rhenium(I) tricarbonyl complexes as potent antibacterial agents against methicillin-resistant Staphylococcus aureus (MRSA). European Journal of Medicinal Chemistry 2020, 205 , 112533. https://doi.org/10.1016/j.ejmech.2020.112533
    38. Nancy Soliman, Vincent Sol, Tan-Sothea Ouk, Christophe M. Thomas, Gilles Gasser. Encapsulation of a Ru(II) Polypyridyl Complex into Polylactide Nanoparticles for Antimicrobial Photodynamic Therapy. Pharmaceutics 2020, 12 (10) , 961. https://doi.org/10.3390/pharmaceutics12100961
    39. Kirsty L. Smitten, Eleanor J. Thick, Hannah M. Southam, Jorge Bernardino de la Serna, Simon J. Foster, Jim A. Thomas. Mononuclear ruthenium( ii ) theranostic complexes that function as broad-spectrum antimicrobials in therapeutically resistant pathogens through interaction with DNA. Chemical Science 2020, 11 (33) , 8828-8838. https://doi.org/10.1039/D0SC03410J
    40. Kirsty L. Smitten, Paul A. Scattergood, Charlotte Kiker, Jim A. Thomas, Paul I. P. Elliott. Triazole-based osmium( ii ) complexes displaying red/near-IR luminescence: antimicrobial activity and super-resolution imaging. Chemical Science 2020, 11 (33) , 8928-8935. https://doi.org/10.1039/D0SC03563G
    41. Angelo Frei, Johannes Zuegg, Alysha G. Elliott, Murray Baker, Stefan Braese, Christopher Brown, Feng Chen, Christopher G. Dowson, Gilles Dujardin, Nicole Jung, A. Paden King, Ahmed M. Mansour, Massimiliano Massi, John Moat, Heba A. Mohamed, Anna K. Renfrew, Peter J. Rutledge, Peter J. Sadler, Matthew H. Todd, Charlotte E. Willans, Justin J. Wilson, Matthew A. Cooper, Mark A. T. Blaskovich. Metal complexes as a promising source for new antibiotics. Chemical Science 2020, 11 (10) , 2627-2639. https://doi.org/10.1039/C9SC06460E
    42. Angelo Frei, Maite Amado, Matthew A. Cooper, Mark A. T. Blaskovich. Light‐Activated Rhenium Complexes with Dual Mode of Action against Bacteria. Chemistry – A European Journal 2020, 26 (13) , 2852-2858. https://doi.org/10.1002/chem.201904689
    43. Zeinab Breijyeh, Buthaina Jubeh, Rafik Karaman. Resistance of Gram-Negative Bacteria to Current Antibacterial Agents and Approaches to Resolve It. Molecules 2020, 25 (6) , 1340. https://doi.org/10.3390/molecules25061340
    44. Hiwa K Saeed, Sreejesh Sreedharan, Jim A Thomas. Photoactive metal complexes that bind DNA and other biomolecules as cell probes, therapeutics, and theranostics. Chemical Communications 2020, 56 (10) , 1464-1480. https://doi.org/10.1039/C9CC09312E
    45. Angelo Frei. Metal Complexes, an Untapped Source of Antibiotic Potential?. Antibiotics 2020, 9 (2) , 90. https://doi.org/10.3390/antibiotics9020090
    46. Kirsty L. Smitten, Simon D. Fairbanks, Craig C. Robertson, Jorge Bernardino de la Serna, Simon J. Foster, Jim A. Thomas. Ruthenium based antimicrobial theranostics – using nanoscopy to identify therapeutic targets and resistance mechanisms in Staphylococcus aureus. Chemical Science 2020, 11 (1) , 70-79. https://doi.org/10.1039/C9SC04710G
    47. David Lloyd, Coralie O. Millet, Catrin F. Williams, Anthony J. Hayes, Simon J.A. Pope, Iestyn Pope, Paola Borri, Wolfgang Langbein, Lars Folke Olsen, Marc D. Isaacs, Anita Lunding. Functional imaging of a model unicell: Spironucleus vortens as an anaerobic but aerotolerant flagellated protist. 2020, 41-79. https://doi.org/10.1016/bs.ampbs.2020.01.002
    48. Paul Güntzel, Christoph Nagel, Jeanette Weigelt, Jono W. Betts, Calum A. Pattrick, Hannah M. Southam, Roberto M. La Ragione, Robert K. Poole, Ulrich Schatzschneider. Biological activity of manganese( i ) tricarbonyl complexes on multidrug-resistant Gram-negative bacteria: From functional studies to in vivo activity in Galleria mellonella. Metallomics 2019, 11 (12) , 2033-2042. https://doi.org/10.1039/C9MT00224C
    49. Biyun Sun, Madhu K. Sundaraneedi, Hannah M. Southam, Robert K. Poole, Ian F. Musgrave, F. Richard Keene, J. Grant Collins. Synthesis and biological properties of tetranuclear ruthenium complexes containing the bis[4(4′-methyl-2,2′-bipyridyl)]-1,7-heptane ligand. Dalton Transactions 2019, 48 (38) , 14505-14515. https://doi.org/10.1039/C9DT03221E

    Pair your accounts.

    Export articles to Mendeley

    Get article recommendations from ACS based on references in your Mendeley library.

    Pair your accounts.

    Export articles to Mendeley

    Get article recommendations from ACS based on references in your Mendeley library.

    You’ve supercharged your research process with ACS and Mendeley!

    STEP 1:
    Click to create an ACS ID

    Please note: If you switch to a different device, you may be asked to login again with only your ACS ID.

    Please note: If you switch to a different device, you may be asked to login again with only your ACS ID.

    Please note: If you switch to a different device, you may be asked to login again with only your ACS ID.

    MENDELEY PAIRING EXPIRED
    Your Mendeley pairing has expired. Please reconnect