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 - Funding Information: This work was partly supported by a DFG grant: HE 7607/1.1 . The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. Funding Information: This work was partly supported by a DFG grant: HE 7607/1.1. The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.We acknowledge support by Deutsche Forschungsgemeinschaft and Open Access Publishing Fund of the University of T?bingen. The authors thank all participants and the staff of the Albert Schweitzer Hospital and CERMEL (Lambar?n?, Gabon) for their help and support. Funding Information: We acknowledge support by Deutsche Forschungsgemeinschaft and Open Access Publishing Fund of the University of Tübingen . The authors thank all participants and the staff of the Albert Schweitzer Hospital and CERMEL (Lambaréné, Gabon) for their help and support. Publisher Copyright: © 2020 The Author(s)
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.
KW - Animals
KW - Anti-Bacterial Agents/pharmacology
KW - Humans
KW - Malaria
KW - Parasites
KW - Plasmodium falciparum/genetics
KW - Tetracycline/pharmacology
KW - Tetracyclines/pharmacology
UR - http://www.scopus.com/inward/record.url?scp=85098593788&partnerID=8YFLogxK
U2 - https://doi.org/10.1016/j.jgar.2020.11.024
DO - https://doi.org/10.1016/j.jgar.2020.11.024
M3 - Article
C2 - 33301999
SN - 2213-7165
VL - 24
SP - 93
EP - 97
JO - Journal of global antimicrobial resistance
JF - Journal of global antimicrobial resistance
ER -