Drug Action and Drug Resistance in Bacteria. 2: Aminoglycoside Antibiotics. Susumu Mitsuhashi

1976 ◽  
Vol 51 (2) ◽  
pp. 314-314
Author(s):  
Alex Bollen
Keyword(s):  
Drug Resistance ◽  
Drug Action ◽  
Aminoglycoside Antibiotics

Probing the methotrexate–protein interactions by proteomics and thermostability assay for drug resistance study

2021 ◽  
Author(s):  
Wenbo Zhang ◽  
Xiaoying Li ◽  
Xiaolei Zhang ◽  
Yan Dong ◽  
Lianghai Hu
Keyword(s):  
Drug Resistance ◽  
Protein Interactions ◽  
Quantitative Proteomics ◽  
Drug Action ◽  
Novel Strategy

Quantitative proteomics combined with thermostability assay provide a novel strategy for the study of mechanisms on drug action and resistance.

scholarly journals Comprehensive profiling of mutations to influenza virus PB2 that confer resistance to the cap-binding inhibitor pimodivir

2021 ◽  
Author(s):  
Y.Q. Shirleen Soh ◽  
Keara D. Malone ◽  
Rachel T. Eguia ◽  
Jesse D Bloom
Keyword(s):  
Drug Resistance ◽  
Influenza A ◽  
Basic Protein ◽  
Drug Action ◽  
Current Treatment ◽  
Single Amino Acid ◽  
Resistance Mutations ◽  
First Line ◽  
Drug Resistance Mutations ◽  
Amino Acid Mutations

Antivirals are used not only in current treatment of influenza, but are also stockpiled as a first line of defense against novel influenza strains for which vaccines have yet to be developed. Identifying drug resistance mutations can guide clinical deployment of the antiviral, and additionally define the mechanisms of drug action and drug resistance. Pimodivir is a first-in-class inhibitor of the polymerase basic protein 2 (PB2) subunit of the influenza A virus polymerase complex. A number of resistance mutations have previously been identified in treated patients or cell culture. Here, we generate a complete map of the effect of all single-amino-acid mutations to an avian PB2 on resistance to pimodivir. We identified both known and novel resistance mutations not only in the previously implicated cap-binding and mid-link domains, but also in the N-terminal domain. Our complete map of pimodivir resistance thus enables the evaluation of whether new viral strains contain mutations that will confer pimodivir resistance.

The interactions between drugs and the parasite surface

Parasitology ◽  
1988 ◽  
Vol 96 (S1) ◽  
pp. S167-S193 ◽  
Author(s):  
L. H. Chappell
Keyword(s):  
Drug Resistance ◽  
Drug Target ◽  
Drug Acquisition ◽  
Drug Action ◽  
Drug Uptake ◽  
Specific Drug ◽  
Permeability Changes ◽  
And Function ◽  
Uptake Mechanisms

SUMMARYThe interrelationships between drugs and parasite surfaces are considered under the headings of (a) effects on membrane transport, (b) drug uptake mechanisms and (c) effects on surface morphology and function: praziquantel is discussed under a separate heading. The range of chemotherapeutic compounds that cause permeability changes and concomitant morphological disruption is discussed in terms of mode of drug action. Interpretation of the available data renders it difficult to identify the primary mode of action in the drugs considered. Drug uptake mechanisms are known for relatively few compounds; drug resistance as a function of drug acquisition is discussed. The role of the parasite surface as a specific drug target is argued.

scholarly journals Rapidly induced drug adaptation mediates escape from BRAF inhibition in single melanoma cells

2020 ◽  
Author(s):  
Chen Yang ◽  
Chengzhe Tian ◽  
Timothy E. Hoffman ◽  
Nicole K. Jacobsen ◽  
Sabrina L. Spencer
Keyword(s):  
Cell Cycle ◽  
Drug Resistance ◽  
Genetic Factors ◽  
Melanoma Cells ◽  
Drug Action ◽  
Cancer Therapies ◽  
Braf Inhibitors ◽  
Braf Inhibition ◽  
Anti Cancer ◽  
Early Drug

AbstractDespite increasing numbers of effective anti-cancer therapies, successful treatment is limited by the development of drug resistance. While the contribution of genetic factors to drug resistance is undeniable, little is known about how drug-sensitive cells first evade drug action to proliferate in drug. Here we track the response of thousands of single melanoma cells to BRAF inhibitors and show that a subset escapes drug within the first 3 days of treatment. Cell-cycle re-entry occurs via a non-genetic mechanism involving activation of mTORC1 and ATF4, validated in cultures of patient biopsies. These escapees cycle periodically in drug, incur significant DNA damage, and out-proliferate non-escapees over extended treatment. Our work reveals a mutagenesis-prone, expanding subpopulation of early drug escapees that may seed development of permanent drug resistance.

scholarly journals Chemogenomic profiling of anti-leishmanial efficacy and resistance in the related kinetoplastid parasite Trypanosoma brucei

2019 ◽  
Author(s):  
Clare F Collett ◽  
Carl Kitson ◽  
Nicola Baker ◽  
Heather B. Steele-Stallard ◽  
Marie-Victoire Santrot ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Amphotericin B ◽  
Trypanosoma Brucei ◽  
Mode Of Action ◽  
Drug Action ◽  
Drug Uptake ◽  
Screening Tools ◽  
Cross Resistance ◽  
Starting Point ◽  
Kinetoplastid Parasite

AbstractThe arsenal of drugs used to treat leishmaniasis, caused by Leishmania spp., is limited and beset by toxicity and emergent resistance. Furthermore, our understanding of drug mode-of-action and potential routes to resistance is limited. Forward genetic approaches have revolutionised our understanding of drug mode-of-action in the related kinetoplastid parasite, Trypanosoma brucei. Therefore, we screened our genome-scale T. brucei RNAi library in the current anti-leishmanial drugs, sodium stibogluconate (antimonial), paromomycin, miltefosine and amphotericin-B. Identification of T. brucei orthologues of the known Leishmania antimonial and miltefosine plasma membrane transporters effectively validated our approach, while a cohort of 42 novel drug efficacy determinants provides new insights and serves as a resource. Follow-up analyses revealed the antimonial selectivity of the aquaglyceroporin, TbAQP3. A lysosomal major facilitator superfamily transporter contributes to paromomycin/aminoglycoside efficacy. The vesicle-associated membrane protein, TbVAMP7B, and a flippase contribute to amphotericin-B and miltefosine action, and are potential cross-resistance determinants. Finally, multiple phospholipid-transporting flippases, including the T. brucei orthologue of the Leishmania miltefosine transporter, a putative β-subunit/CDC50 co-factor, and additional membrane-associated hits, affect amphotericin-B efficacy, providing new insights into mechanisms of drug uptake and action. The findings from this orthology-based chemogenomic profiling approach substantially advance our understanding of anti-leishmanial drug action and potential resistance mechanisms, and should facilitate the development of improved therapies, as well as surveillance for drug-resistant parasites.ImportanceLeishmaniasis is a devastating disease caused by the Leishmania parasites and is endemic to a wide swathe of the tropics and sub-tropics. While there are drugs available for the treatment of leishmaniasis, these suffer from various challenges, including the spread of drug resistance. Our understanding of anti-leishmanial drug action and the modes of drug resistance in Leishmania is limited. The development of genetic screening tools in the related parasite, Trypanosoma brucei, has revolutionised our understanding of these processes in this parasite. Therefore, we applied these tools to the anti-leishmanial drugs, identifying T. brucei orthologues of known Leishmania proteins that drive drug uptake, as well as a panel of novel proteins not previously associated with anti-leishmanial drug action. Our findings substantially advance our understanding of anti-leishmanial mode-of-action and provide a valuable starting point for further research.

Helminth detoxification mechanisms

1997 ◽  
Vol 71 (2) ◽  
pp. 85-90 ◽  
Author(s):  
J. Barrett
Keyword(s):  
Drug Resistance ◽  
Drug Development ◽  
Selective Inhibition ◽  
Drug Action ◽  
Detoxification Enzymes ◽  
Defence Mechanisms ◽  
Parasitic Helminths ◽  
Protective Enzymes ◽  
Detoxification Mechanisms

Detoxification mechanisms in parasitic helminths have not been extensively studied, despite their obvious relevance to drug development and drug resistance. Differences in detoxification enzymes between the parasite and its host may be exploitable in the design of pro-drugs, whilst selective inhibition of the parasites protective enzymes could increase their sensitivity to drug action and also make them more susceptible to the host's defence mechanisms.

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