In vitro activity of eravacycline, a novel synthetic halogenated tetracycline, against the malaria parasite Plasmodium falciparum

Objectives: Eravacycline is a novel synthetic halogenated tetracycline derivative with a broad antibacterial spectrum. Antibiotics, including tetracyclines, have been used for prophylaxis and, more rarely, for the treatment of malaria for several decades. The rise in drug-resistant malaria parasites...

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Main Authors: Erik Koehne, Andrea Kreidenweiss, Bayode Romeo Adegbite, Rella Zoleko Manego, Matthew B.B. McCall, Ghyslain Mombo-Ngoma, Ayola Akim Adegnika, Sélidji Todagbé Agnandji, Benjamin Mordmüller, Jana Held
Format: Article
Language:English
Published: Elsevier 2021-03-01
Series:Journal of Global Antimicrobial Resistance
Subjects:
Online Access:http://www.sciencedirect.com/science/article/pii/S2213716520303106
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language English
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author Erik Koehne
Andrea Kreidenweiss
Bayode Romeo Adegbite
Rella Zoleko Manego
Matthew B.B. McCall
Ghyslain Mombo-Ngoma
Ayola Akim Adegnika
Sélidji Todagbé Agnandji
Benjamin Mordmüller
Jana Held
spellingShingle Erik Koehne
Andrea Kreidenweiss
Bayode Romeo Adegbite
Rella Zoleko Manego
Matthew B.B. McCall
Ghyslain Mombo-Ngoma
Ayola Akim Adegnika
Sélidji Todagbé Agnandji
Benjamin Mordmüller
Jana Held
In vitro activity of eravacycline, a novel synthetic halogenated tetracycline, against the malaria parasite Plasmodium falciparum
Journal of Global Antimicrobial Resistance
Plasmodium falciparum
Eravacycline
Tetracycline
Isopentenyl pyrophosphate
Malaria
author_facet Erik Koehne
Andrea Kreidenweiss
Bayode Romeo Adegbite
Rella Zoleko Manego
Matthew B.B. McCall
Ghyslain Mombo-Ngoma
Ayola Akim Adegnika
Sélidji Todagbé Agnandji
Benjamin Mordmüller
Jana Held
author_sort Erik Koehne
title In vitro activity of eravacycline, a novel synthetic halogenated tetracycline, against the malaria parasite Plasmodium falciparum
title_short In vitro activity of eravacycline, a novel synthetic halogenated tetracycline, against the malaria parasite Plasmodium falciparum
title_full In vitro activity of eravacycline, a novel synthetic halogenated tetracycline, against the malaria parasite Plasmodium falciparum
title_fullStr In vitro activity of eravacycline, a novel synthetic halogenated tetracycline, against the malaria parasite Plasmodium falciparum
title_full_unstemmed In vitro activity of eravacycline, a novel synthetic halogenated tetracycline, against the malaria parasite Plasmodium falciparum
title_sort in vitro activity of eravacycline, a novel synthetic halogenated tetracycline, against the malaria parasite plasmodium falciparum
publisher Elsevier
series Journal of Global Antimicrobial Resistance
issn 2213-7165
publishDate 2021-03-01
description Objectives: Eravacycline is a novel synthetic halogenated tetracycline derivative with a broad antibacterial spectrum. Antibiotics, including tetracyclines, have been used for prophylaxis and, more rarely, for the treatment of malaria for several decades. The rise in drug-resistant malaria parasites renders the search for new treatment candidates urgent. We determined the in vitro potency of eravacycline against Plasmodium falciparum and investigated the apicoplast as a potential drug target. Methods: Four tetracyclines, including eravacycline, tetracycline, tigecycline, and doxycycline, and the lincosamide clindamycin, were tested in 3-day and 6-day in vitro susceptibility assays of P. falciparum laboratory strain 3D7 and/or of clinical isolates obtained from 33 P. falciparum infected individuals from Gabon in 2018. Assays with isopentenyl pyrophosphate substitution were performed to investigate whether apicoplast-encoded isoprenoid biosynthesis is inhibited by these antibiotics. Results: Eravacycline showed the highest activity of all tetracyclines tested in clinical isolates in the 3-day and 6-day assays. Substitution of isopentenyl pyrophosphate in vitro using the laboratory strain 3D7 reversed the activity of eravacycline and comparator antibiotics, indicating the apicoplast to be the main target organelle. Conclusions: These results demonstrate the potential of novel antibiotics, and eravacycline, as candidate antimalarial therapies.
topic Plasmodium falciparum
Eravacycline
Tetracycline
Isopentenyl pyrophosphate
Malaria
url http://www.sciencedirect.com/science/article/pii/S2213716520303106
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spelling doaj-5f396db5dc224c23a90809c125387fba2021-06-09T05:58:08ZengElsevierJournal of Global Antimicrobial Resistance2213-71652021-03-01249397In vitro activity of eravacycline, a novel synthetic halogenated tetracycline, against the malaria parasite Plasmodium falciparumErik Koehne0Andrea Kreidenweiss1Bayode Romeo Adegbite2Rella Zoleko Manego3Matthew B.B. McCall4Ghyslain Mombo-Ngoma5Ayola Akim Adegnika6Sélidji Todagbé Agnandji7Benjamin Mordmüller8Jana Held9Institute of Tropical Medicine, Eberhard Karls University Tübingen, Wilhelmstraße 27, D-72074 Tübingen, Germany; Centre de Recherches Médicales de Lambaréné, B.P. 242, Lambaréné, Gabon; German Center for Infection Research, partner site Tübingen, Wilhelmstraße 27, D-72074 Tübingen, GermanyInstitute of Tropical Medicine, Eberhard Karls University Tübingen, Wilhelmstraße 27, D-72074 Tübingen, Germany; Centre de Recherches Médicales de Lambaréné, B.P. 242, Lambaréné, Gabon; German Center for Infection Research, partner site Tübingen, Wilhelmstraße 27, D-72074 Tübingen, GermanyCentre de Recherches Médicales de Lambaréné, B.P. 242, Lambaréné, GabonCentre de Recherches Médicales de Lambaréné, B.P. 242, Lambaréné, Gabon; Department of Tropical Medicine, Bernhard Nocht Institute for Tropical Medicine & I. Dep of Medicine, University Medical Center Hamburg-Eppendorf, Bernhard-Nocht-Straße 74, D-20359 Hamburg, GermanyInstitute of Tropical Medicine, Eberhard Karls University Tübingen, Wilhelmstraße 27, D-72074 Tübingen, Germany; Centre de Recherches Médicales de Lambaréné, B.P. 242, Lambaréné, Gabon; German Center for Infection Research, partner site Tübingen, Wilhelmstraße 27, D-72074 Tübingen, GermanyInstitute of Tropical Medicine, Eberhard Karls University Tübingen, Wilhelmstraße 27, D-72074 Tübingen, Germany; Centre de Recherches Médicales de Lambaréné, B.P. 242, Lambaréné, Gabon; Department of Tropical Medicine, Bernhard Nocht Institute for Tropical Medicine & I. Dep of Medicine, University Medical Center Hamburg-Eppendorf, Bernhard-Nocht-Straße 74, D-20359 Hamburg, GermanyInstitute of Tropical Medicine, Eberhard Karls University Tübingen, Wilhelmstraße 27, D-72074 Tübingen, Germany; Centre de Recherches Médicales de Lambaréné, B.P. 242, Lambaréné, Gabon; German Center for Infection Research, partner site Tübingen, Wilhelmstraße 27, D-72074 Tübingen, GermanyInstitute of Tropical Medicine, Eberhard Karls University Tübingen, Wilhelmstraße 27, D-72074 Tübingen, Germany; Centre de Recherches Médicales de Lambaréné, B.P. 242, Lambaréné, Gabon; German Center for Infection Research, partner site Tübingen, Wilhelmstraße 27, D-72074 Tübingen, GermanyInstitute of Tropical Medicine, Eberhard Karls University Tübingen, Wilhelmstraße 27, D-72074 Tübingen, Germany; Centre de Recherches Médicales de Lambaréné, B.P. 242, Lambaréné, Gabon; German Center for Infection Research, partner site Tübingen, Wilhelmstraße 27, D-72074 Tübingen, GermanyInstitute of Tropical Medicine, Eberhard Karls University Tübingen, Wilhelmstraße 27, D-72074 Tübingen, Germany; Centre de Recherches Médicales de Lambaréné, B.P. 242, Lambaréné, Gabon; German Center for Infection Research, partner site Tübingen, Wilhelmstraße 27, D-72074 Tübingen, Germany; Corresponding author at: Institute of Tropical Medicine, Eberhard-Karls University, Wilhelmstraße 27, D-72074 Tübingen, Germany.Objectives: Eravacycline is a novel synthetic halogenated tetracycline derivative with a broad antibacterial spectrum. Antibiotics, including tetracyclines, have been used for prophylaxis and, more rarely, for the treatment of malaria for several decades. The rise in drug-resistant malaria parasites renders the search for new treatment candidates urgent. We determined the in vitro potency of eravacycline against Plasmodium falciparum and investigated the apicoplast as a potential drug target. Methods: Four tetracyclines, including eravacycline, tetracycline, tigecycline, and doxycycline, and the lincosamide clindamycin, were tested in 3-day and 6-day in vitro susceptibility assays of P. falciparum laboratory strain 3D7 and/or of clinical isolates obtained from 33 P. falciparum infected individuals from Gabon in 2018. Assays with isopentenyl pyrophosphate substitution were performed to investigate whether apicoplast-encoded isoprenoid biosynthesis is inhibited by these antibiotics. Results: Eravacycline showed the highest activity of all tetracyclines tested in clinical isolates in the 3-day and 6-day assays. Substitution of isopentenyl pyrophosphate in vitro using the laboratory strain 3D7 reversed the activity of eravacycline and comparator antibiotics, indicating the apicoplast to be the main target organelle. Conclusions: These results demonstrate the potential of novel antibiotics, and eravacycline, as candidate antimalarial therapies.http://www.sciencedirect.com/science/article/pii/S2213716520303106Plasmodium falciparumEravacyclineTetracyclineIsopentenyl pyrophosphateMalaria