Antimicrobial Activity of a Repurposed Harmine-Derived Compound on Carbapenem-Resistant Acinetobacter baumannii Clinical Isolates

Anke Breine; Mégane Van Gysel; Mathias Elsocht; Clémence Whiteway; Chantal Philippe; Théo Quinet; Adam Valcek; Johan Wouters; Steven Ballet; Charles Van der Henst

doi:10.3389/fcimb.2021.789672

Antimicrobial Activity of a Repurposed Harmine-Derived Compound on Carbapenem-Resistant Acinetobacter baumannii Clinical Isolates

Anke Breine, Mégane Van Gysel, Mathias Elsocht, Clémence Whiteway, Chantal Philippe, Théo Quinet, Adam Valcek, Johan Wouters, Steven Ballet, Charles Van der Henst

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

Abstract

Objectives: The spread of antibiotic resistant bacteria is an important threat for human health. Acinetobacter baumannii bacteria impose such a major issue, as multidrug- to pandrug-resistant strains have been isolated, rendering some infections untreatable. In this context, carbapenem-resistant A. baumannii bacteria were ranked as top priority by both WHO and CDC. In addition, A. baumannii bacteria survive in harsh environments, being capable of resisting to disinfectants and to persist prolonged periods of desiccation. Due to the high degree of variability found in A. baumannii isolates, the search for new antibacterials is very challenging because of the requirement of drug target conservation amongst the different strains. Here, we screened a chemical library to identify compounds active against several reference strains and carbapenem-resistant A. baumannii bacteria. Methods: A repurposing drug screen was undertaken to identify A. baumannii growth inhibitors. One hit was further characterized by determining the IC₅₀ and testing the activity on 43 modern clinical A. baumannii isolates, amongst which 40 are carbapenem-resistant. Results: The repurposing screen led to the identification of a harmine-derived compound, called HDC1, which proves to have bactericidal activity on the multidrug-resistant AB5075-VUB reference strain with an IC₅₀ of 48.23 µM. In addition, HDC1 impairs growth of 43 clinical A. baumannii isolates. Conclusions: We identified a compound with inhibitory activity on all tested strains, including carbapenem-resistant clinical A. baumannii isolates.

Original language	English
Article number	789672
Journal	Frontiers in cellular and infection microbiology
Volume	11
DOIs	https://doi.org/10.3389/fcimb.2021.789672
Publication status	Published - 24 Jan 2022

Funding

We are grateful to Pr. Tom Coenye for providing us the strain AB5075 and Dr. Suzana Salcedo for the strains ATCC19606, ATCC17978 and DSM30011, as well as for fruitful discussions. We would like to thank Pr. Pierre Bogaerts, Pr. Te-din Huang and Pr. Olivier Denis, from the National Reference Center (NRC) Laboratory for Antibiotic-Resistant Gram-Negative Bacilli (CHU UCL Namur, Yvoir, Belgium) for providing the recent clinical isolates of A. baumannii. We also thank the members of Namedic (NARILIS-UNamur), in particular Pr. B. Masereel and L. Pochet for their research that allowed setting up the chemical library used in the present screening. AB is recipient of a PhD fellowship Strategic Basic Research of the Research Foundation – Flanders (FWO, File number: 77258). ME and SB acknowledge financial support of the Research Council at the Vrije Universiteit Brussel (VUB) through the IRP funding scheme. CV acknowledges the financial support from the Flanders Institute for Biotechnology (VIB). This project has received funding from the European Union’s Horizon 2020 research and innovation program under the Marie Sklodowska-Curie grant agreement No 748032.

Keywords

Acinetobacter baumannii
carbapenem-resistant
drug screening
Gram-negative
pathogenic bacteria
repurposed compound

UN SDGs

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

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10.3389/fcimb.2021.789672

Cite this

Breine, A., Van Gysel, M., Elsocht, M., Whiteway, C., Philippe, C., Quinet, T., Valcek, A., Wouters, J., Ballet, S., & Van der Henst, C. (2022). Antimicrobial Activity of a Repurposed Harmine-Derived Compound on Carbapenem-Resistant Acinetobacter baumannii Clinical Isolates. Frontiers in cellular and infection microbiology, 11, Article 789672. https://doi.org/10.3389/fcimb.2021.789672

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abstract = "Objectives: The spread of antibiotic resistant bacteria is an important threat for human health. Acinetobacter baumannii bacteria impose such a major issue, as multidrug- to pandrug-resistant strains have been isolated, rendering some infections untreatable. In this context, carbapenem-resistant A. baumannii bacteria were ranked as top priority by both WHO and CDC. In addition, A. baumannii bacteria survive in harsh environments, being capable of resisting to disinfectants and to persist prolonged periods of desiccation. Due to the high degree of variability found in A. baumannii isolates, the search for new antibacterials is very challenging because of the requirement of drug target conservation amongst the different strains. Here, we screened a chemical library to identify compounds active against several reference strains and carbapenem-resistant A. baumannii bacteria. Methods: A repurposing drug screen was undertaken to identify A. baumannii growth inhibitors. One hit was further characterized by determining the IC50 and testing the activity on 43 modern clinical A. baumannii isolates, amongst which 40 are carbapenem-resistant. Results: The repurposing screen led to the identification of a harmine-derived compound, called HDC1, which proves to have bactericidal activity on the multidrug-resistant AB5075-VUB reference strain with an IC50 of 48.23 µM. In addition, HDC1 impairs growth of 43 clinical A. baumannii isolates. Conclusions: We identified a compound with inhibitory activity on all tested strains, including carbapenem-resistant clinical A. baumannii isolates.",

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Breine, A, Van Gysel, M, Elsocht, M, Whiteway, C, Philippe, C , Quinet, T, Valcek, A, Wouters, J, Ballet, S & Van der Henst, C 2022, 'Antimicrobial Activity of a Repurposed Harmine-Derived Compound on Carbapenem-Resistant Acinetobacter baumannii Clinical Isolates', Frontiers in cellular and infection microbiology, vol. 11, 789672. https://doi.org/10.3389/fcimb.2021.789672

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T1 - Antimicrobial Activity of a Repurposed Harmine-Derived Compound on Carbapenem-Resistant Acinetobacter baumannii Clinical Isolates

AU - Breine, Anke

AU - Van Gysel, Mégane

AU - Elsocht, Mathias

AU - Whiteway, Clémence

AU - Philippe, Chantal

AU - Quinet, Théo

AU - Valcek, Adam

AU - Wouters, Johan

AU - Ballet, Steven

AU - Van der Henst, Charles

PY - 2022/1/24

Y1 - 2022/1/24

N2 - Objectives: The spread of antibiotic resistant bacteria is an important threat for human health. Acinetobacter baumannii bacteria impose such a major issue, as multidrug- to pandrug-resistant strains have been isolated, rendering some infections untreatable. In this context, carbapenem-resistant A. baumannii bacteria were ranked as top priority by both WHO and CDC. In addition, A. baumannii bacteria survive in harsh environments, being capable of resisting to disinfectants and to persist prolonged periods of desiccation. Due to the high degree of variability found in A. baumannii isolates, the search for new antibacterials is very challenging because of the requirement of drug target conservation amongst the different strains. Here, we screened a chemical library to identify compounds active against several reference strains and carbapenem-resistant A. baumannii bacteria. Methods: A repurposing drug screen was undertaken to identify A. baumannii growth inhibitors. One hit was further characterized by determining the IC50 and testing the activity on 43 modern clinical A. baumannii isolates, amongst which 40 are carbapenem-resistant. Results: The repurposing screen led to the identification of a harmine-derived compound, called HDC1, which proves to have bactericidal activity on the multidrug-resistant AB5075-VUB reference strain with an IC50 of 48.23 µM. In addition, HDC1 impairs growth of 43 clinical A. baumannii isolates. Conclusions: We identified a compound with inhibitory activity on all tested strains, including carbapenem-resistant clinical A. baumannii isolates.

AB - Objectives: The spread of antibiotic resistant bacteria is an important threat for human health. Acinetobacter baumannii bacteria impose such a major issue, as multidrug- to pandrug-resistant strains have been isolated, rendering some infections untreatable. In this context, carbapenem-resistant A. baumannii bacteria were ranked as top priority by both WHO and CDC. In addition, A. baumannii bacteria survive in harsh environments, being capable of resisting to disinfectants and to persist prolonged periods of desiccation. Due to the high degree of variability found in A. baumannii isolates, the search for new antibacterials is very challenging because of the requirement of drug target conservation amongst the different strains. Here, we screened a chemical library to identify compounds active against several reference strains and carbapenem-resistant A. baumannii bacteria. Methods: A repurposing drug screen was undertaken to identify A. baumannii growth inhibitors. One hit was further characterized by determining the IC50 and testing the activity on 43 modern clinical A. baumannii isolates, amongst which 40 are carbapenem-resistant. Results: The repurposing screen led to the identification of a harmine-derived compound, called HDC1, which proves to have bactericidal activity on the multidrug-resistant AB5075-VUB reference strain with an IC50 of 48.23 µM. In addition, HDC1 impairs growth of 43 clinical A. baumannii isolates. Conclusions: We identified a compound with inhibitory activity on all tested strains, including carbapenem-resistant clinical A. baumannii isolates.

KW - Acinetobacter baumannii

KW - carbapenem-resistant

KW - drug screening

KW - Gram-negative

KW - pathogenic bacteria

KW - repurposed compound

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ER -

Antimicrobial Activity of a Repurposed Harmine-Derived Compound on Carbapenem-Resistant Acinetobacter baumannii Clinical Isolates

Abstract

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Keywords

UN SDGs

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Physical Chemistry and characterization(PC2)

Cite this

Antimicrobial Activity of a Repurposed Harmine-Derived Compound on Carbapenem-Resistant Acinetobacter baumannii Clinical Isolates

Abstract

Funding

Keywords

UN SDGs

Access to Document

Other files and links

Fingerprint

Equipment

Physical Chemistry and characterization(PC2)

Cite this