In vivo active organometallic-containing antimycotic agents

Riccardo Rubbiani; Tobias Weil; Noemi Tocci; Luciano Mastrobuoni; Severin Jeger; Marco Moretto; James Ng; Yan Lin; Jeannine Hess; Stefano Ferrari; Andres Kaech; Luke Young; John Spencer; Anthony L. Moore; Kevin Cariou; Giorgia Renga; Marilena Pariano; Luigina Romani; Gilles Gasser

doi:10.1039/d1cb00123j

In vivo active organometallic-containing antimycotic agents

Riccardo Rubbiani^*, Tobias Weil, Noemi Tocci, Luciano Mastrobuoni, Severin Jeger, Marco Moretto, James Ng, Yan Lin, Jeannine Hess, Stefano Ferrari, Andres Kaech, Luke Young, John Spencer, Anthony L. Moore, Kevin Cariou, Giorgia Renga, Marilena Pariano, Luigina Romani, Gilles Gasser

^*Corresponding author for this work

Chemistry

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

5 Citations (Scopus)

Abstract

Fungal infections represent a global problem, notably for immunocompromised patients in hospital, COVID-19 patient wards and care home settings, and the ever-increasing emergence of multidrug resistant fungal strains is a sword of Damocles hanging over many healthcare systems. Azoles represent the mainstay of antifungal drugs, and their mode of action involves the binding mode of these molecules to the fungal lanosterol 14α-demethylase target enzyme. In this study, we have prepared and characterized four novel organometallic derivatives of the frontline antifungal drug fluconazole (1a-4a). Very importantly, enzyme inhibition and chemogenomic profiling demonstrated that lanosterol 14α-demethylase, as for fluconazole, was the main target of the most active compound of the series, (N-(ferrocenylmethyl)-2-(2,4-difluorophenyl)-2-hydroxy-N-methyl-3-(1H-1,2,4-triazol-1-yl)propan-1-aminium chloride, 2a). Transmission electron microscopy (TEM) studies suggested that 2a induced a loss in cell wall integrity as well as intracellular features ascribable to late apoptosis or necrosis. The impressive activity of 2a was further confirmed on clinical isolates, where antimycotic potency up to 400 times higher than fluconazole was observed. Also, 2a showed activity towards azole-resistant strains. This finding is very interesting since the primary target of 2a is the same as that of fluconazole, emphasizing the role played by the organometallic moiety. In vivo experiments in a mice model of Candida infections revealed that 2a reduced the fungal growth and dissemination but also ameliorated immunopathology, a finding suggesting that 2a is active in vivo with added activity on the host innate immune response. This journal is

Original language	English
Pages (from-to)	1263-1273
Number of pages	11
Journal	RSC Chemical Biology
Volume	2
Issue number	4
DOIs	https://doi.org/10.1039/d1cb00123j
Publication status	Published - Aug 2021

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10.1039/d1cb00123j

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@article{9d541f0ef1484063923efa71d4ed3761,

title = "In vivo active organometallic-containing antimycotic agents",

abstract = "Fungal infections represent a global problem, notably for immunocompromised patients in hospital, COVID-19 patient wards and care home settings, and the ever-increasing emergence of multidrug resistant fungal strains is a sword of Damocles hanging over many healthcare systems. Azoles represent the mainstay of antifungal drugs, and their mode of action involves the binding mode of these molecules to the fungal lanosterol 14α-demethylase target enzyme. In this study, we have prepared and characterized four novel organometallic derivatives of the frontline antifungal drug fluconazole (1a-4a). Very importantly, enzyme inhibition and chemogenomic profiling demonstrated that lanosterol 14α-demethylase, as for fluconazole, was the main target of the most active compound of the series, (N-(ferrocenylmethyl)-2-(2,4-difluorophenyl)-2-hydroxy-N-methyl-3-(1H-1,2,4-triazol-1-yl)propan-1-aminium chloride, 2a). Transmission electron microscopy (TEM) studies suggested that 2a induced a loss in cell wall integrity as well as intracellular features ascribable to late apoptosis or necrosis. The impressive activity of 2a was further confirmed on clinical isolates, where antimycotic potency up to 400 times higher than fluconazole was observed. Also, 2a showed activity towards azole-resistant strains. This finding is very interesting since the primary target of 2a is the same as that of fluconazole, emphasizing the role played by the organometallic moiety. In vivo experiments in a mice model of Candida infections revealed that 2a reduced the fungal growth and dissemination but also ameliorated immunopathology, a finding suggesting that 2a is active in vivo with added activity on the host innate immune response. This journal is ",

author = "Riccardo Rubbiani and Tobias Weil and Noemi Tocci and Luciano Mastrobuoni and Severin Jeger and Marco Moretto and James Ng and Yan Lin and Jeannine Hess and Stefano Ferrari and Andres Kaech and Luke Young and John Spencer and Moore, {Anthony L.} and Kevin Cariou and Giorgia Renga and Marilena Pariano and Luigina Romani and Gilles Gasser",

note = "Funding Information: This work was funded by the Swiss National Science Foundation (Grant Sinergia CRSII5_173718, Professorships No. PP00P2_133568 and PP00P2_157545 to G. G.), the University of Zurich (G. G.), the Stiftung f{\"u}r Wissenschaftliche Forschung of the University of Zurich (G. G.), the Novartis Jubilee Foundation (G. G. and R. R.), the Forschungskredit of the University of Zurich (R. R.) and the UBS Promedica Stiftung (G. G. and R. R.). This work has received support under the program {\textquoteleft}{\textquoteleft}Investisse-ments d{\textquoteright}Avenir{\textquoteright}{\textquoteright} launched by the French Government and implemented by the ANR with the reference ANR-10-IDEX-0001-02 PSL (G. G.). This research was supported by the Autonomous Province of Trento (Accordo di Programma P1611051I (M. M.)). Work in A. L. M.{\textquoteright}s laboratory is supported by BBSRC (BB/L022915/1 and BB/NO10051/1). The authors thank Monica Borghi for her technical assistance for the mice experiments. We would also like to thank the University of Sussex (HEIF COVID-19 emergency funds) and the Ewart Bequest Fund for this work (J. S.). Publisher Copyright: {\textcopyright} The Royal Society of Chemistry.",

year = "2021",

month = aug,

doi = "10.1039/d1cb00123j",

language = "English",

volume = "2",

pages = "1263--1273",

journal = "RSC Chemical Biology",

issn = "2633-0679",

publisher = "Royal Society of Chemistry",

number = "4",

}

TY - JOUR

T1 - In vivo active organometallic-containing antimycotic agents

AU - Rubbiani, Riccardo

AU - Weil, Tobias

AU - Tocci, Noemi

AU - Mastrobuoni, Luciano

AU - Jeger, Severin

AU - Moretto, Marco

AU - Ng, James

AU - Lin, Yan

AU - Hess, Jeannine

AU - Ferrari, Stefano

AU - Kaech, Andres

AU - Young, Luke

AU - Spencer, John

AU - Moore, Anthony L.

AU - Cariou, Kevin

AU - Renga, Giorgia

AU - Pariano, Marilena

AU - Romani, Luigina

AU - Gasser, Gilles

N1 - Funding Information: This work was funded by the Swiss National Science Foundation (Grant Sinergia CRSII5_173718, Professorships No. PP00P2_133568 and PP00P2_157545 to G. G.), the University of Zurich (G. G.), the Stiftung für Wissenschaftliche Forschung of the University of Zurich (G. G.), the Novartis Jubilee Foundation (G. G. and R. R.), the Forschungskredit of the University of Zurich (R. R.) and the UBS Promedica Stiftung (G. G. and R. R.). This work has received support under the program ‘‘Investisse-ments d’Avenir’’ launched by the French Government and implemented by the ANR with the reference ANR-10-IDEX-0001-02 PSL (G. G.). This research was supported by the Autonomous Province of Trento (Accordo di Programma P1611051I (M. M.)). Work in A. L. M.’s laboratory is supported by BBSRC (BB/L022915/1 and BB/NO10051/1). The authors thank Monica Borghi for her technical assistance for the mice experiments. We would also like to thank the University of Sussex (HEIF COVID-19 emergency funds) and the Ewart Bequest Fund for this work (J. S.). Publisher Copyright: © The Royal Society of Chemistry.

PY - 2021/8

Y1 - 2021/8

N2 - Fungal infections represent a global problem, notably for immunocompromised patients in hospital, COVID-19 patient wards and care home settings, and the ever-increasing emergence of multidrug resistant fungal strains is a sword of Damocles hanging over many healthcare systems. Azoles represent the mainstay of antifungal drugs, and their mode of action involves the binding mode of these molecules to the fungal lanosterol 14α-demethylase target enzyme. In this study, we have prepared and characterized four novel organometallic derivatives of the frontline antifungal drug fluconazole (1a-4a). Very importantly, enzyme inhibition and chemogenomic profiling demonstrated that lanosterol 14α-demethylase, as for fluconazole, was the main target of the most active compound of the series, (N-(ferrocenylmethyl)-2-(2,4-difluorophenyl)-2-hydroxy-N-methyl-3-(1H-1,2,4-triazol-1-yl)propan-1-aminium chloride, 2a). Transmission electron microscopy (TEM) studies suggested that 2a induced a loss in cell wall integrity as well as intracellular features ascribable to late apoptosis or necrosis. The impressive activity of 2a was further confirmed on clinical isolates, where antimycotic potency up to 400 times higher than fluconazole was observed. Also, 2a showed activity towards azole-resistant strains. This finding is very interesting since the primary target of 2a is the same as that of fluconazole, emphasizing the role played by the organometallic moiety. In vivo experiments in a mice model of Candida infections revealed that 2a reduced the fungal growth and dissemination but also ameliorated immunopathology, a finding suggesting that 2a is active in vivo with added activity on the host innate immune response. This journal is

AB - Fungal infections represent a global problem, notably for immunocompromised patients in hospital, COVID-19 patient wards and care home settings, and the ever-increasing emergence of multidrug resistant fungal strains is a sword of Damocles hanging over many healthcare systems. Azoles represent the mainstay of antifungal drugs, and their mode of action involves the binding mode of these molecules to the fungal lanosterol 14α-demethylase target enzyme. In this study, we have prepared and characterized four novel organometallic derivatives of the frontline antifungal drug fluconazole (1a-4a). Very importantly, enzyme inhibition and chemogenomic profiling demonstrated that lanosterol 14α-demethylase, as for fluconazole, was the main target of the most active compound of the series, (N-(ferrocenylmethyl)-2-(2,4-difluorophenyl)-2-hydroxy-N-methyl-3-(1H-1,2,4-triazol-1-yl)propan-1-aminium chloride, 2a). Transmission electron microscopy (TEM) studies suggested that 2a induced a loss in cell wall integrity as well as intracellular features ascribable to late apoptosis or necrosis. The impressive activity of 2a was further confirmed on clinical isolates, where antimycotic potency up to 400 times higher than fluconazole was observed. Also, 2a showed activity towards azole-resistant strains. This finding is very interesting since the primary target of 2a is the same as that of fluconazole, emphasizing the role played by the organometallic moiety. In vivo experiments in a mice model of Candida infections revealed that 2a reduced the fungal growth and dissemination but also ameliorated immunopathology, a finding suggesting that 2a is active in vivo with added activity on the host innate immune response. This journal is

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U2 - 10.1039/d1cb00123j

DO - 10.1039/d1cb00123j

M3 - Article

AN - SCOPUS:85112184772

SN - 2633-0679

VL - 2

SP - 1263

EP - 1273

JO - RSC Chemical Biology

JF - RSC Chemical Biology

IS - 4

ER -

In vivo active organometallic-containing antimycotic agents

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