scholarly journals In Vitro Selection of Highly Darunavir-Resistant and Replication-Competent HIV-1 Variants by Using a Mixture of Clinical HIV-1 Isolates Resistant to Multiple Conventional Protease Inhibitors

2010 ◽  
Vol 84 (22) ◽  
pp. 11961-11969 ◽  
Author(s):  
Yasuhiro Koh ◽  
Masayuki Amano ◽  
Tomomi Towata ◽  
Matthew Danish ◽  
Sofiya Leshchenko-Yashchuk ◽  
...  
Keyword(s):  
Homologous Recombination ◽  
In Vitro Selection ◽  
Multiple Drug ◽  
Drug Resistant ◽  
Genetic Barrier ◽  
Development Of Resistance ◽  
Multiple Drug Resistant ◽  
Moderately Resistant ◽  
Hiv 1

ABSTRACT We attempted to select HIV-1 variants resistant to darunavir (DRV), which potently inhibits the enzymatic activity and dimerization of protease and has a high genetic barrier to HIV-1 development of resistance to DRV. We conducted selection using a mixture of 8 highly multi-protease inhibitor (PI)-resistant, DRV-susceptible clinical HIV-1 variants (HIV-1MIX) containing 9 to 14 PI resistance-associated amino acid substitutions in protease. HIV-1MIX became highly resistant to DRV, with a 50% effective concentration (EC50) ∼333-fold greater than that against HIV-1NL4-3. HIV-1MIX at passage 51 (HIV-1MIXP51 ) replicated well in the presence of 5 μM DRV and contained 14 mutations. HIV-1MIXP51 was highly resistant to amprenavir, indinavir, nelfinavir, ritonavir, lopinavir, and atazanavir and moderately resistant to saquinavir and tipranavir. HIV-1MIXP51 had a resemblance with HIV-1C of the HIV-1MIX population, and selection using HIV-1C was also performed; however, its DRV resistance acquisition was substantially delayed. The H219Q and I223V substitutions in Gag, lacking in HIV-1CP51 , likely contributed to conferring a replication advantage on HIV-1MIXP51 by reducing intravirion cyclophilin A content. HIV-1MIXP51 apparently acquired the substitutions from another HIV-1 strain(s) of HIV-1MIX through possible homologous recombination. The present data suggest that the use of multiple drug-resistant HIV-1 isolates is of utility in selecting drug-resistant variants and that DRV would not easily permit HIV-1 to develop significant resistance; however, HIV-1 can develop high levels of DRV resistance when a variety of PI-resistant HIV-1 strains are generated, as seen in patients experiencing sequential PI failure, and ensuing homologous recombination takes place. HIV-1MIXP51 should be useful in elucidating the mechanisms of HIV-1 resistance to DRV and related agents.

scholarly journals Antitumor mechanism of evodiamine, a constituent from Chinese herb Evodiae fructus , in human multiple-drug resistant breast cancer NCI/ADR-RES cells in vitro and in vivo

2005 ◽  
Vol 26 (5) ◽  
pp. 968-975 ◽  
Author(s):  
Cho-Hwa Liao ◽  
Shiow-Lin Pan ◽  
Jih-Hwa Guh ◽  
Ya-Ling Chang ◽  
Hui-Chen Pai ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Chinese Herb ◽  
Multiple Drug ◽  
Drug Resistant ◽  
Multiple Drug Resistant

scholarly journals Klebsiella virus UPM2146 lyses multiple drug-resistant Klebsiella pneumoniae in vitro and in vivo

PLoS ONE ◽  
2021 ◽  
Vol 16 (1) ◽  
pp. e0245354
Author(s):  
Omar Assafiri ◽  
Adelene Ai-Lian Song ◽  
Geok Hun Tan ◽  
Irwan Hanish ◽  
Amalia Mohd Hashim ◽  
...  
Keyword(s):  
Klebsiella Pneumoniae ◽  
Multiple Drug ◽  
Drug Resistant ◽  
Zebrafish Model ◽  
Whole Genome Analysis ◽  
Narrow Host Range ◽  
Opportunistic Bacteria ◽  
Multiple Drug Resistant

Klebsiella pneumoniae are opportunistic bacteria found in the gut. In recent years they have been associated with nosocomial infections. The increased incidence of multiple drug-resistant K. pneumoniae makes it necessary to find new alternatives to treat the disease. In this study, phage UPM2146 was isolated from a polluted lake which can lyse its host K. pneumoniae ATCC BAA-2146. Observation from TEM shows that UPM2146 belongs to Caudoviriales (Order) based on morphological appearance. Whole genome analysis of UPM2146 showed that its genome comprises 160,795 bp encoding for 214 putative open reading frames (ORFs). Phylogenetic analysis revealed that the phage belongs to Ackermannviridae (Family) under the Caudoviriales. UPM2146 produces clear plaques with high titers of 1010 PFU/ml. The phage has an adsorption period of 4 min, latent period of 20 min, rise period of 5 min, and releases approximately 20 PFU/ bacteria at Multiplicity of Infection (MOI) of 0.001. UPM2146 has a narrow host-range and can lyse 5 out of 22 K. pneumoniae isolates (22.72%) based on spot test and efficiency of plating (EOP). The zebrafish larvae model was used to test the efficacy of UPM2146 in lysing its host. Based on colony forming unit counts, UPM2146 was able to completely lyse its host at 10 hours onwards. Moreover, we show that the phage is safe to be used in the treatment against K. pneumoniae infections in the zebrafish model.

scholarly journals TMC125 Displays a High Genetic Barrier to the Development of Resistance: Evidence from In Vitro Selection Experiments

2005 ◽  
Vol 79 (20) ◽  
pp. 12773-12782 ◽  
Author(s):  
Johan Vingerhoets ◽  
Hilde Azijn ◽  
Els Fransen ◽  
Inky De Baere ◽  
Liesbet Smeulders ◽  
...  
Keyword(s):  
Wild Type Virus ◽  
Cross Resistance ◽  
Resistant Virus ◽  
Wild Type ◽  
Genetic Barrier ◽  
Development Of Resistance ◽  
Selection Experiments ◽  
The Impact ◽  
Hiv 1

ABSTRACT TMC125 is a potent new investigational nonnucleoside reverse transcriptase inhibitor (NNRTI) that is active against human immunodeficiency virus type 1 (HIV-1) with resistance to currently licensed NNRTIs. Sequential passage experiments with both wild-type virus and NNRTI-resistant virus were performed to identify mutations selected by TMC125 in vitro. In addition to “classic” selection experiments at a low multiplicity of infection (MOI) with increasing concentrations of inhibitors, experiments at a high MOI with fixed concentrations of inhibitors were performed to ensure a standardized comparison between TMC125 and current NNRTIs. Both low- and high-MOI experiments demonstrated that the development of resistance to TMC125 required multiple mutations which frequently conferred cross-resistance to efavirenz and nevirapine. In high-MOI experiments, 1 μM TMC125 completely inhibited the breakthrough of resistant virus from wild-type and NNRTI-resistant HIV-1, in contrast to efavirenz and nevirapine. Furthermore, breakthrough of virus from site-directed mutant (SDM) SDM-K103N/Y181C occurred at the same time or later with TMC125 as breakthrough from wild-type HIV-1 with efavirenz or nevirapine. The selection experiments identified mutations selected by TMC125 that included known NNRTI-associated mutations L100I, Y181C, G190E, M230L, and Y318F and the novel mutations V179I and V179F. Testing the antiviral activity of TMC125 against a panel of SDMs indicated that the impact of these individual mutations on resistance was highly dependent upon the presence and identity of coexisting mutations. These results demonstrate that TMC125 has a unique profile of activity against NNRTI-resistant virus and possesses a high genetic barrier to the development of resistance in vitro.

scholarly journals A marine microbiome antifungal targets urgent-threat drug-resistant fungi

Science ◽  
2020 ◽  
Vol 370 (6519) ◽  
pp. 974-978 ◽  
Author(s):  
Fan Zhang ◽  
Miao Zhao ◽  
Doug R. Braun ◽  
Spencer S. Ericksen ◽  
Jeff S. Piotrowski ◽  
...  
Keyword(s):  
Mode Of Action ◽  
Fungal Pathogens ◽  
Antifungal Drugs ◽  
Multiple Drug ◽  
Drug Resistant ◽  
Candida Auris ◽  
Marine Animals ◽  
Multiple Drug Resistant

New antifungal drugs are urgently needed to address the emergence and transcontinental spread of fungal infectious diseases, such as pandrug-resistant Candida auris. Leveraging the microbiomes of marine animals and cutting-edge metabolomics and genomic tools, we identified encouraging lead antifungal molecules with in vivo efficacy. The most promising lead, turbinmicin, displays potent in vitro and mouse-model efficacy toward multiple-drug–resistant fungal pathogens, exhibits a wide safety index, and functions through a fungal-specific mode of action, targeting Sec14 of the vesicular trafficking pathway. The efficacy, safety, and mode of action distinct from other antifungal drugs make turbinmicin a highly promising antifungal drug lead to help address devastating global fungal pathogens such as C. auris.

Pre-exposure prophylaxis failure with a multiple drug-resistant HIV-1 clade C virus in Brazil

2021 ◽  
Vol Publish Ahead of Print ◽  
Author(s):  
Ricardo Sohbie Diaz ◽  
Alexandre Grangeiro ◽  
Denize Lotufo Estevam ◽  
Juliana Galinskas ◽  
Danilo Dias ◽  
...  
Keyword(s):  
Multiple Drug ◽  
Drug Resistant ◽  
Multiple Drug Resistant ◽  
Clade C ◽  
Exposure Prophylaxis ◽  
Hiv 1
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