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drug resistance

  • Acetylation of Isoniazid Is a Novel Mechanism of Isoniazid Resistance in <span class="named-content genus-species" id="named-content-1">Mycobacterium tuberculosis</span>
    Mechanisms of Resistance
    Acetylation of Isoniazid Is a Novel Mechanism of Isoniazid Resistance in Mycobacterium tuberculosis

    Isoniazid (INH), one of the first-line drugs used for the treatment of tuberculosis, is a prodrug which is activated by the intracellular KatG enzyme of Mycobacterium tuberculosis. The activated drug hinders cell wall biosynthesis by inhibiting the InhA protein. INH-resistant strains of M. tuberculosis...

    K. B. Arun, Aravind Madhavan, Billu Abraham, M. Balaji, K. C. Sivakumar, P. Nisha, R. Ajay Kumar
  • Open Access
    Tolerance of Gambian <span class="named-content genus-species" id="named-content-1">Plasmodium falciparum</span> to Dihydroartemisinin and Lumefantrine Detected by <em>Ex Vivo</em> Parasite Survival Rate Assay
    Susceptibility
    Tolerance of Gambian Plasmodium falciparum to Dihydroartemisinin and Lumefantrine Detected by Ex Vivo Parasite Survival Rate Assay

    Monitoring of Plasmodium falciparum sensitivity to antimalarial drugs in Africa is vital for malaria elimination. However, the commonly used ex vivo/in vitro 50% inhibitory concentration (IC50) test gives inconsistent results for several antimalarials, while the alternative ring-stage survival assay (RSA) for artemisinin derivatives has...

    Haddijatou Mbye, Fatoumata Bojang, Aminata Seedy Jawara, Bekai Njie, Nuredin Ibrahim Mohammed, Joseph Okebe, Umberto D’Alessandro, Alfred Amambua-Ngwa
  • Open Access
    Small-Molecule Inhibitors of Chikungunya Virus: Mechanisms of Action and Antiviral Drug Resistance
    Minireview
    Small-Molecule Inhibitors of Chikungunya Virus: Mechanisms of Action and Antiviral Drug Resistance

    Chikungunya virus (CHIKV) is a mosquito-transmitted alphavirus that has spread to more than 60 countries worldwide. CHIKV infection leads to a febrile illness known as chikungunya fever (CHIKF), which is characterized by long-lasting and debilitating joint and muscle pain. CHIKV can cause large-scale epidemics with high attack rates, which substantiates the need for development of effective therapeutics suitable for outbreak containment...

    Kristina Kovacikova, Martijn J. van Hemert
  • Open Access
    Natural Polymorphisms in <span class="named-content genus-species" id="named-content-1">Mycobacterium tuberculosis</span> Conferring Resistance to Delamanid in Drug-Naive Patients
    Susceptibility
    Natural Polymorphisms in Mycobacterium tuberculosis Conferring Resistance to Delamanid in Drug-Naive Patients

    Mutations in the genes of the F420 signaling pathway of Mycobacterium tuberculosis complex, including dnn, fgd1, fbiA, fbiB, fbiC, and fbiD, can lead to delamanid resistance. We searched for such mutations among 129 M. tuberculosis...

    Martina L. Reichmuth, Rico Hömke, Kathrin Zürcher, Peter Sander, Anchalee Avihingsanon, Jimena Collantes, Chloé Loiseau, Sonia Borrell, Miriam Reinhard, Robert J. Wilkinson, Marcel Yotebieng, Lukas Fenner, Erik C. Böttger, Sebastien Gagneux, Matthias Egger, Peter M. Keller
    and on behalf of the International epidemiology Databases to Evaluate AIDS (IeDEA)
  • Associations between Aminoquinoline Resistance Genotypes and Clinical Presentations of <span class="named-content genus-species" id="named-content-1">Plasmodium falciparum</span> Infection in Uganda
    Mechanisms of Resistance
    Associations between Aminoquinoline Resistance Genotypes and Clinical Presentations of Plasmodium falciparum Infection in Uganda

    Mutations that mediate resistance of Plasmodium falciparum to aminoquinoline antimalarials are selected by prior drug use and may alter parasite fitness, but associations with clinical presentations are uncertain. We evaluated genotypes in samples from a case-control study of determinants of severe malaria in Ugandan children 4 months to 10 years of age. We studied...

    Gloria Cuu, Victor Asua, Stephen Tukwasibwe, Sam L. Nsobya, Ann Nanteza, Magambo Phillip Kimuda, Arthur Mpimbaza, Philip J. Rosenthal
  • Nucleocapsid Protein Precursors NCp9 and NCp15 Suppress ATP-Mediated Rescue of AZT-Terminated Primers by HIV-1 Reverse Transcriptase
    Antiviral Agents
    Nucleocapsid Protein Precursors NCp9 and NCp15 Suppress ATP-Mediated Rescue of AZT-Terminated Primers by HIV-1 Reverse Transcriptase

    In HIV-1, development of resistance to AZT (3′-azido-3′-deoxythymidine) is mediated by the acquisition of thymidine analogue resistance mutations (TAMs) (i.e., M41L, D67N, K70R, L210W, T215F/Y, and K219E/Q) in the viral reverse transcriptase (RT). Clinically relevant combinations of TAMs, such as M41L/T215Y or D67N/K70R/T215F/K219Q, enhance the ATP-mediated excision of AZT monophosphate (AZTMP) from the 3′ end of the primer, allowing...

    Moisés A. Árquez, Samara Martín-Alonso, Robert J. Gorelick, Walter A. Scott, Antonio J. Acosta-Hoyos, Luis Menéndez-Arias
  • Open Access
    HIV Coinfection Is Associated with Low-Fitness <em>rpoB</em> Variants in Rifampicin-Resistant <span class="named-content genus-species" id="named-content-1">Mycobacterium tuberculosis</span>
    Epidemiology and Surveillance
    HIV Coinfection Is Associated with Low-Fitness rpoB Variants in Rifampicin-Resistant Mycobacterium tuberculosis

    We analyzed 312 drug-resistant genomes of Mycobacterium tuberculosis isolates collected from HIV-coinfected and HIV-negative TB patients from nine countries with a high tuberculosis burden. We found that rifampicin-resistant M. tuberculosis strains isolated from HIV-coinfected patients carried...

    Chloé Loiseau, Daniela Brites, Miriam Reinhard, Kathrin Zürcher, Sonia Borrell, Marie Ballif, Lukas Fenner, Helen Cox, Liliana K. Rutaihwa, Robert J. Wilkinson, Marcel Yotebieng, E. Jane Carter, Alash'le Abimiku, Olivier Marcy, Eduardo Gotuzzo, Anchalee Avihingsanon, Nicola Zetola, Basra Doulla, Erik C. Böttger, Matthias Egger, Sebastien Gagneux
  • HIV-1 Integrase Inhibitors That Are Active against Drug-Resistant Integrase Mutants
    Antiviral Agents
    HIV-1 Integrase Inhibitors That Are Active against Drug-Resistant Integrase Mutants

    The currently recommended first-line therapy for HIV-1-infected patients is an integrase (IN) strand transfer inhibitor (INSTI), either dolutegravir (DTG) or bictegravir (BIC), in combination with two nucleoside reverse transcriptase inhibitors (NRTIs). Both DTG and BIC potently inhibit most INSTI-resistant IN mutants selected by the INSTIs raltegravir (RAL) and elvitegravir (EVG). BIC has not been reported to select for resistance in...

    Steven J. Smith, Xue Zhi Zhao, Dario Oliveira Passos, Dmitry Lyumkis, Terrence R. Burke, Stephen H. Hughes
  • A Multimethod, Multicountry Evaluation of Breakpoints for Bedaquiline Resistance Determination
    Clinical Therapeutics
    A Multimethod, Multicountry Evaluation of Breakpoints for Bedaquiline Resistance Determination

    Criteria defining bedaquiline resistance for tuberculosis have been proposed addressing an emerging concern. We evaluated bedaquiline phenotypic drug susceptibility testing (pDST) criteria using drug-resistant tuberculosis clinical isolates tested at five reference laboratories. Isolates were tested at the proposed bedaquiline MGIT960 and 7H11 agar proportion (AP) critical concentrations and also at higher dilutions. The epidemiological...

    Nazir Ahmed Ismail, Akio Aono, Emanuele Borroni, Daniela Maria Cirillo, Christel Desmaretz, Rumina Hasan, Satoshi Mitarai, Sadia Shakoor, Gabriela Torrea, Koné Kaniga, Shaheed V. Omar
  • Rapidly Correcting Frameshift Mutations in the <span class="named-content genus-species" id="named-content-1">Mycobacterium tuberculosis</span> <em>orn</em> Gene Produce Reversible Ethambutol Resistance and Small-Colony-Variant Morphology
    Editor's Pick Mechanisms of Resistance
    Rapidly Correcting Frameshift Mutations in the Mycobacterium tuberculosis orn Gene Produce Reversible Ethambutol Resistance and Small-Colony-Variant Morphology

    We have identified a previously unknown mechanism of reversible high-level ethambutol (EMB) resistance in Mycobacterium tuberculosis that is caused by a reversible frameshift mutation in the M. tuberculosis orn gene. A frameshift mutation in orn produces the small-colony-variant (...

    Hassan Safi, Subramanya Lingaraju, Shuyi Ma, Seema Husain, Mainul Hoque, Patricia Soteropoulos, Tige Rustad, David R. Sherman, David Alland

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