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

TY - JOUR

T1 - In vitro activity of eravacycline, a novel synthetic halogenated tetracycline, against the malaria parasite Plasmodium falciparum

AU - Koehne, Erik

AU - Kreidenweiss, Andrea

AU - Adegbite, Bayode Romeo

AU - Manego, Rella Zoleko

AU - McCall, Matthew B B

AU - Mombo-Ngoma, Ghyslain

AU - Adegnika, Ayola Akim

AU - Agnandji, Sélidji Todagbé

AU - Mordmüller, Benjamin

AU - Held, Jana

N1 - Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.

PY - 2021/3

Y1 - 2021/3

N2 - 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.

AB - 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.

U2 - 10.1016/j.jgar.2020.11.024

DO - 10.1016/j.jgar.2020.11.024

M3 - SCORING: Journal article

C2 - 33301999

VL - 24

SP - 93

EP - 97

JO - J GLOB ANTIMICROB RE

JF - J GLOB ANTIMICROB RE

SN - 2213-7165

ER -