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Start Over Topic drug resistance Publication Year Range Last 10 years
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1. MDR M. tuberculosis outbreak clone in Eswatini missed by Xpert has elevated bedaquiline resistance dated to the pre-treatment era

Author

Elisabeth Sanchez-Padilla, Nazir Ahmed Ismail, Thomas Kohl, Christian Utpatel, Patrick Beckert, Stefan Niemann, Claudio U. Köser, Harald Hoffmann, Sönke Andres, Robin M. Warren, Bouke C. de Jong, Marisa Klopper, Matthias Merker, Florian P. Maurer, Shaheed V. Omar, Katharina Kranzer, Maryline Bonnet, Bernhard Kerschberger, Viola Dreyer, Ivan Barilar, Elisa Ardizzoni, Birgit Schramm, Gugu Maphalala, Forschungszentrum Borstel - Research Center Borstel, German Center for Infection Research (DZIF), Heidelberg University, Epicentre [Paris] [Médecins Sans Frontières], University of Cambridge [UK] (CAM), National Institute for Communicable Diseases [Johannesburg] (NICD), University of Pretoria [South Africa], University of the Witwatersrand [Johannesburg] (WITS), Stellenbosch University, Institute of Tropical Medicine [Antwerp] (ITM), London School of Hygiene and Tropical Medicine (LSHTM), Universitaetsklinikum Hamburg-Eppendorf = University Medical Center Hamburg-Eppendorf [Hamburg] (UKE), Recherches Translationnelles sur le VIH et les maladies infectieuses endémiques et émergentes (TransVIHMI), Université Montpellier 1 (UM1)-Institut de Recherche pour le Développement (IRD)-Université de Yaoundé I-Université Cheikh Anta Diop [Dakar, Sénégal] (UCAD)-Institut National de la Santé et de la Recherche Médicale (INSERM), Infectious and Tropical Diseases Department [Montpellier], Institut de Recherche pour le Développement (IRD)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Namibia (UNAM), Parts of this work have been supported by the European Union TB-PAN-NET (FP7-223681) project, by Médecins Sans Frontières-Switzerland, and by German Center for Infection Research, Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germanys Excellence Strategy – EXC 2167, and Leibniz Science Campus Evolutionary Medicine of the LUNG (EvoLUNG). The funders had no role in the study design, in the collection, analysis, and interpretation of the data, in the writing of the report, and in the decision to submit the paper for publication., European Project: 223681,EC:FP7:HEALTH,FP7-HEALTH-2007-B,TB PAN-NET(2009), Niemann, Stefan [0000-0002-6604-0684], and Apollo - University of Cambridge Repository

Subjects
0301 basic medicine, MESH: Mycobacterium tuberculosis, Antitubercular Agents, Drug resistance, Multidrug resistance, Disease Outbreaks, Clofazimine, chemistry.chemical_compound, Tuberculosis, Multidrug-Resistant, MESH: Disease Outbreaks, Diarylquinolines, MESH: Bacterial Proteins, Genetics (clinical), MESH: Microbial Sensitivity Tests, Resistance mutation, MESH: Diarylquinolines, Mycobacterium tuberculosis complex, Molecular Medicine, medicine.drug, MESH: Mutation, Tuberculosis, 030106 microbiology, Microbial Sensitivity Tests, Biology, 03 medical and health sciences, Bacterial Proteins, MESH: Eswatini, Genetics, medicine, Humans, Molecular Biology, MESH: Tuberculosis, Multidrug-Resistant, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Humans, Diagnostice escape, Research, MESH: Clone Cells, Resistance evolution, Treatment escape, Mycobacterium tuberculosis, rpoB, medicine.disease, biology.organism_classification, MESH: Antitubercular Agents, Virology, Clone Cells, Multiple drug resistance, MDR outbreak strains, 030104 developmental biology, chemistry, Treatment failure, Mutation, Bedaquiline, Eswatini
Abstract

Background Multidrug-resistant (MDR) Mycobacterium tuberculosis complex strains not detected by commercial molecular drug susceptibility testing (mDST) assays due to the RpoB I491F resistance mutation are threatening the control of MDR tuberculosis (MDR-TB) in Eswatini. Methods We investigate the evolution and spread of MDR strains in Eswatini with a focus on bedaquiline (BDQ) and clofazimine (CFZ) resistance using whole-genome sequencing in two collections ((1) national drug resistance survey, 2009–2010; (2) MDR strains from the Nhlangano region, 2014–2017). Results MDR strains in collection 1 had a high cluster rate (95%, 117/123 MDR strains) with 55% grouped into the two largest clusters (gCL3, n = 28; gCL10, n = 40). All gCL10 isolates, which likely emerged around 1993 (95% highest posterior density 1987–1998), carried the mutation RpoB I491F that is missed by commercial mDST assays. In addition, 21 (53%) gCL10 isolates shared a Rv0678 M146T mutation that correlated with elevated minimum inhibitory concentrations (MICs) to BDQ and CFZ compared to wild type isolates. gCL10 isolates with the Rv0678 M146T mutation were also detected in collection 2. Conclusion The high clustering rate suggests that transmission has been driving the MDR-TB epidemic in Eswatini for three decades. The presence of MDR strains in Eswatini that are not detected by commercial mDST assays and have elevated MICs to BDQ and CFZ potentially jeopardizes the successful implementation of new MDR-TB treatment guidelines. Measures to limit the spread of these outbreak isolates need to be implemented urgently.

Published
2020

2. Plasmepsin II–III copy number accounts for bimodal piperaquine resistance among Cambodian Plasmodium falciparum

Author

Bopp, S, Magistrado, P, Wong, W, Schaffner, S, Mukherjee, A, Lim, P, Dhorda, M, Amaratunga, C, Woodrow, C, Ashley, E, White, N, Dondorp, A, Fairhurst, R, Ariey, F, Menard, D, Wirth, D, Volkman, S, Harvard T.H. Chan School of Public Health, Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], National Institutes of Health [Bethesda] (NIH), WWARN Asia Regional Centre [Bangkok, Thailand], Mahidol University [Bangkok], Mahidol Oxford Tropical Medicine Research Unit, University of Oxford-Mahidol University [Bangkok], Myanmar Oxford Clinical Research Unit [Yangon, Myanmar], Centre for Tropical Medicine and Global Health [Oxford, UK], Nuffield Department of Medicine [Oxford, UK] (Big Data Institute), University of Oxford-University of Oxford, Mahidol Oxford Tropical Medicine Research Unit (MORU), University of Oxford-Mahidol University [Bangkok]-Wellcome Trust, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Biologie des Interactions Hôte-Parasite - Biology of Host-Parasite Interactions, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Simmons college, This work was supported in part by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health., We thank Courtney Edison for slide reading and subcloning the KH001_053 isolate., The computations in this paper were run on the Odyssey cluster supported by the FAS Division of Science, Research Computing Group at Harvard University. N.J.W., C.J.W. were supported by Bill and Melinda Gates Foundation Global Health Grant Number OPP1040463, which also funded culture adaptation of the parasites described herein. Additional support was provided to DFW by the Bill and Melinda Gates Foundation Global Health Grant Number OPP1053604. This document is an output from a project of the Tracking Resistance to Artemisinin Collaboration funded by the UK Department for International Development (DFID) for the benefit of developing countries. However, the views expressed and information contained in it are not necessarily those of or endorsed by DFID, which can accept no responsibility for such views or for any reliance place on them., University of Oxford [Oxford]-Mahidol University [Bangkok], University of Oxford [Oxford]-University of Oxford [Oxford], Wellcome Trust-Mahidol University [Bangkok]-University of Oxford [Oxford], and Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Infectious-disease epidemiology, DNA Copy Number Variations, Whole Genome Sequencing, Cell Survival, Science, Plasmodium falciparum, Drug Resistance, Gene Dosage, Protozoan Proteins, Article, Malaria, Target validation, Isoenzymes, Antimalarials, parasitic diseases, Quinolines, Aspartic Acid Endopeptidases, Humans, lcsh:Q, [SDV.MP.PAR]Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, lcsh:Science, Cambodia, Antiparasitic agents
Abstract

Multidrug resistant Plasmodium falciparum in Southeast Asia endangers regional malaria elimination and threatens to spread to other malaria endemic areas. Understanding mechanisms of piperaquine (PPQ) resistance is crucial for tracking its emergence and spread, and to develop effective strategies for overcoming it. Here we analyze a mechanism of PPQ resistance in Cambodian parasites. Isolates exhibit a bimodal dose–response curve when exposed to PPQ, with the area under the curve quantifying their survival in vitro. Increased copy number for plasmepsin II and plasmepsin III appears to explain enhanced survival when exposed to PPQ in most, but not all cases. A panel of isogenic subclones reinforces the importance of plasmepsin II–III copy number to enhanced PPQ survival. We conjecture that factors producing increased parasite survival under PPQ exposure in vitro may drive clinical PPQ failures in the field., Piperaquine (PPQ) resistance of Plasmodium is an increasing problem. Here, Bopp et al. find a bimodal dose−response curve of Cambodian isolates exposed to PPQ, with the area under the curve correlating with in vitro PPQ resistance, and show the importance of Plasmepsin II–III copy number to PPQ resistance.

Published
2018