drug resistance
Mechanisms of ResistanceAcetylation of Isoniazid Is a Novel Mechanism of Isoniazid Resistance in Mycobacterium tuberculosisIsoniazid (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...
SusceptibilityTolerance of Gambian Plasmodium falciparum to Dihydroartemisinin and Lumefantrine Detected by Ex Vivo Parasite Survival Rate AssayMonitoring 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...
MinireviewSmall-Molecule Inhibitors of Chikungunya Virus: Mechanisms of Action and Antiviral Drug ResistanceChikungunya 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...
SusceptibilityNatural Polymorphisms in Mycobacterium tuberculosis Conferring Resistance to Delamanid in Drug-Naive PatientsMutations 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...
Mechanisms of ResistanceAssociations between Aminoquinoline Resistance Genotypes and Clinical Presentations of Plasmodium falciparum Infection in UgandaMutations 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...
Antiviral AgentsNucleocapsid Protein Precursors NCp9 and NCp15 Suppress ATP-Mediated Rescue of AZT-Terminated Primers by HIV-1 Reverse TranscriptaseIn 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...
Epidemiology and SurveillanceHIV Coinfection Is Associated with Low-Fitness rpoB Variants in Rifampicin-Resistant Mycobacterium tuberculosisWe 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...
Antiviral AgentsHIV-1 Integrase Inhibitors That Are Active against Drug-Resistant Integrase MutantsThe 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...
Clinical TherapeuticsA Multimethod, Multicountry Evaluation of Breakpoints for Bedaquiline Resistance DeterminationCriteria 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...
Editor's Pick Mechanisms of ResistanceRapidly Correcting Frameshift Mutations in the Mycobacterium tuberculosis orn Gene Produce Reversible Ethambutol Resistance and Small-Colony-Variant MorphologyWe 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 (...