scholarly journals Microtubule Targeting Agents in Disease: Classic Drugs, Novel Roles

Cancers ◽  
2021 ◽  
Vol 13 (22) ◽  
pp. 5650
Author(s):  
Linda Wordeman ◽  
Juan Jesus Vicente
Keyword(s):  
Drug Resistance ◽  
Innate Immunity ◽  
Mechanism Of Action ◽  
First Line ◽  
Classical View ◽  
Acquired Drug Resistance ◽  
Limited Success ◽  
Microtubule Targeting Agents ◽  
Proinflammatory Responses ◽  
Slow Growing

Microtubule-targeting agents (MTAs) represent one of the most successful first-line therapies prescribed for cancer treatment. They interfere with microtubule (MT) dynamics by either stabilizing or destabilizing MTs, and in culture, they are believed to kill cells via apoptosis after eliciting mitotic arrest, among other mechanisms. This classical view of MTA therapies persisted for many years. However, the limited success of drugs specifically targeting mitotic proteins, and the slow growing rate of most human tumors forces a reevaluation of the mechanism of action of MTAs. Studies from the last decade suggest that the killing efficiency of MTAs arises from a combination of interphase and mitotic effects. Moreover, MTs have also been implicated in other therapeutically relevant activities, such as decreasing angiogenesis, blocking cell migration, reducing metastasis, and activating innate immunity to promote proinflammatory responses. Two key problems associated with MTA therapy are acquired drug resistance and systemic toxicity. Accordingly, novel and effective MTAs are being designed with an eye toward reducing toxicity without compromising efficacy or promoting resistance. Here, we will review the mechanism of action of MTAs, the signaling pathways they affect, their impact on cancer and other illnesses, and the promising new therapeutic applications of these classic drugs.

scholarly journals High-Levels of Acquired Drug Resistance in Adult Patients Failing First-Line Antiretroviral Therapy in a Rural HIV Treatment Programme in KwaZulu-Natal, South Africa

PLoS ONE ◽  
2013 ◽  
Vol 8 (8) ◽  
pp. e72152 ◽  
Author(s):  
Justen Manasa ◽  
Richard J. Lessells ◽  
Andrew Skingsley ◽  
Kevindra K. Naidu ◽  
Marie-Louise Newell ◽  
...  
Keyword(s):  
South Africa ◽  
Drug Resistance ◽  
Antiretroviral Therapy ◽  
Hiv Treatment ◽  
Adult Patients ◽  
Treatment Programme ◽  
First Line ◽  
Acquired Drug Resistance ◽  
Kwazulu Natal

High rate of virological failure and HIV drug resistance in semi-rural Gabon and implications for dolutegravir-based regimen efficacy

2020 ◽  
Author(s):  
Jéordy D Engone-Ondo ◽  
Augustin Mouinga-Ondémé ◽  
Sonia E Lékana-Douki ◽  
Abdoulaye Diané ◽  
Antony I Mamimandjiami ◽  
...  
Keyword(s):  
Drug Resistance ◽  
High Rate ◽  
Resistance Mutations ◽  
First Line ◽  
Rural Regions ◽  
Hiv Drug Resistance ◽  
Acquired Drug Resistance ◽  
Resource Limited ◽  
Study Population ◽  
Study Participants

Abstract Background The projected UNAIDS goal of ending AIDS by 2030 requires significant global efforts to improve current and future ART strategies. In this study, we assessed viral load (VL) suppression and acquired drug resistance, as well as future efficacy of dolutegravir-based combinations for patients living in semi-rural regions of Gabon. Methods Eligible study participants were adults receiving ART and recruited between 2018 and 2019 in Franceville, Gabon. VL testing was conducted to assess VL suppression and HIV drug resistance (HIVDR) testing was performed to identify resistance mutations and assess their impact on ongoing and future ART regimens. Results We recruited 219 participants overall. The median time on ART was 27 months and 216/219 participants were on first-line ART. VL suppression (VL < 1000 copies/mL) was 57.1% (95% CI 50.5–63.8) overall; 59.4% (51.4–67.5) and 52.2% (40.3–64.2) for women and men, respectively. The overall prevalence of HIVDR was 21.9% among the study population and 67.2% among those who failed ART. Presence of both NRTI and NNRTI mutations was found in 84.6% of sequences with drug resistance mutations, and full activity of a dolutegravir-based first-line regimen including tenofovir disoproxil fumarate/lamivudine/dolutegravir was expected only for 5/39 patients with a resistant virus. Conclusions This study shows a very low rate of VL suppression in a semi-rural context in Africa. Moreover, the high burden of HIVDR has affected both current and newly recommended ART strategies. Better management of ART in resource-limited settings is still a challenging ambition.

scholarly journals Pyrrolomycins Are Potent Natural Protonophores

2019 ◽  
Vol 63 (10) ◽  
Author(s):  
Katherine Valderrama ◽  
Elizabeth Pradel ◽  
Alexander M. Firsov ◽  
Hervé Drobecq ◽  
Hélène Bauderlique-le Roy ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Mechanism Of Action ◽  
Lipid Membrane ◽  
Specific Activity ◽  
Bilayer Lipid Membrane ◽  
Gram Positive ◽  
Content Type ◽  
Acquired Drug Resistance ◽  
Antibiotic Drug ◽  
The Impact

ABSTRACT The escalating burden of antibiotic drug resistance necessitates research into novel classes of antibiotics and their mechanism of action. Pyrrolomycins are a family of potent natural product antibiotics with nanomolar activity against Gram-positive bacteria, yet with an elusive mechanism of action. In this work, we dissect the apparent Gram-positive specific activity of pyrrolomycins and show that Gram-negative bacteria are equally sensitive to pyrrolomycins when drug efflux transporters are removed and that albumin in medium plays a large role in pyrrolomycin activity. The selection of resistant mutants allowed for the characterization and validation of a number of mechanisms of resistance to pyrrolomycins in both Staphylococcus aureus and an Escherichia coli ΔtolC mutant, all of which appear to affect compound penetration rather than being target associated. Imaging of the impact of pyrrolomycin on the E. coli ΔtolC mutant using scanning electron microscopy showed blebbing of the bacterial cell wall often at the site of bacterial division. Using potentiometric probes and an electrophysiological technique with an artificial bilayer lipid membrane, it was demonstrated that pyrrolomycins C and D are very potent membrane-depolarizing agents, an order of magnitude more active than conventional carbonyl cyanide m-chlorophenylhydrazone (CCCP), specifically disturbing the proton gradient and uncoupling oxidative phosphorylation via protonophoric action. This work clearly unveils the until-now-elusive mechanism of action of pyrrolomycins and explains their antibiotic activity as well as mechanisms of innate and acquired drug resistance in bacteria.

scholarly journals Antituberculous Drug Resistance in Western Canada (1993 to 1994)

1997 ◽  
Vol 4 (2) ◽  
pp. 71-75 ◽  
Author(s):  
Richard Long ◽  
Anne Fanning ◽  
Robert Cowie ◽  
Vernon Hoeppner ◽  
Mark Fitzgerald ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Drug Susceptibility Testing ◽  
Resistance Rate ◽  
Western Canada ◽  
Drug Resistant ◽  
Foreign Born ◽  
First Line ◽  
Acquired Drug Resistance ◽  
Antituberculous Drug ◽  
Culture Positive

OBJECTIVES: To estimate the magnitude of antituberculous drug resistance and identify prospectively the risk factors for its development in tuberculosis (TB) patients in western Canada over a one-year period.DESIGN: Comparison of drug-resistant and nondrug-resistant cases of TB.SETTING: Western Canada.PATIENTS: All people with TB reported to the TB registries of Manitoba, British Columbia, Alberta and Saskatchewan between February 1, 1993 and January 31, 1994.MAIN OUTCOME MEASURES: Drug susceptibility testing was performed in all cases of culture-positive tuberculosis. Patients at risk for human immunodeficiency virus (HIV) infection were serotested.RESULTS: Of 534 culture positive cases of TB, 37 (6.9%) were drug resistant. Odds ratios suggested that the risk of drug resistance was significantly higher among those with reactivation than among those with new disease, and among those born outside of Canada than among those born in Canada. Ninety per cent of the foreign-born patients with drug-resistant disease were from Asia. Of the 35 patients with drug resistance whose type of resistance was known, 76% had initial and 24% had acquired drug resistance. The initial resistance rate in Asian-born patients was 14%. Most of the 37 drug-resistant cases were resistant to isoniazid (68%), streptomycin (49%) or both (22%). Twelve (32%) of the 37 cases were resistant to two or more first-line drugs. Of 14 patients who were HIV seropositive only one, a foreign-born patient, was drug resistant.CONCLUSION: Antituberculous drug resistance is low among Canadian-born patients in western Canada, but not uncommon among those born outside Canada. Initial therapy of foreign-born patients should include four first-line drugs.

scholarly journals Rates of HIV-1 virological suppression and patterns of acquired drug resistance among fisherfolk on first-line antiretroviral therapy in Uganda

2019 ◽  
Vol 74 (10) ◽  
pp. 3021-3029 ◽  
Author(s):  
Jonah Omooja ◽  
Maria Nannyonjo ◽  
Grace Sanyu ◽  
Stella E Nabirye ◽  
Faridah Nassolo ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Cost Effective ◽  
Virological Suppression ◽  
First Line ◽  
Acquired Drug Resistance ◽  
Resource Limited ◽  
Adherence Support ◽  
Virological Outcomes ◽  
Pooling Strategies ◽  
Adherence Counselling

AbstractObjectivesWe examined virological outcomes, patterns of acquired HIV drug resistance (ADR), correlates of virological failure (VF) and acquired drug resistance among fisherfolk on first-line ART.MethodsWe enrolled 1169 adults on ART for a median duration of 6, 12, 24, 36 and ≥48 months and used a pooled VL testing approach to identify VF (VL ≥1000 copies/mL). We performed genotyping among VF cases and determined correlates of VF and ADR by logistic regression.ResultsThe overall virological suppression rate was 91.7% and ADR was detected in 71/97 (73.2%) VF cases. The most prevalent mutations were M184V/I (53.6%) for NRTIs and K103N (39.2%) for NNRTIs. Thymidine analogue mutations were detected in 21.6% of VF cases while PI mutations were absent. A zidovudine-based ART regimen, duration on ART (≥24 months) and secondary/higher education level were significantly associated with VF. A nevirapine-based regimen [adjusted OR (aOR): 1.87; 95% CI: 0.03–0.54)] and VL ≥10000 copies/mL (aOR: 3.48; 95% CI: 1.37–8.85) were ADR correlates. The pooling strategies for VL testing with a negative predictive value (NPV) of ≥95.2% saved US $20320 (43.5%) in VL testing costs.ConclusionsWe observed high virological suppression rates among these highly mobile fisherfolk; however, there was widespread ADR among those with VF at the first VL testing prior to intensive adherence counselling. Timely treatment switching and adherence support is recommended for better treatment outcomes. Adoption of pooled VL testing could be cost effective, particularly in resource-limited settings.

Chemistry of antimony-based drugs in biological systems and studies of their mechanism of action

2013 ◽  
Vol 33 (1) ◽  
pp. 1-12 ◽  
Author(s):  
Frédéric Frézard ◽  
Cynthia Demicheli ◽  
Kelly C. Kato ◽  
Priscila G. Reis ◽  
Edgar H. Lizarazo-Jaimes
Keyword(s):  
Molecular Structure ◽  
Drug Resistance ◽  
Mechanism Of Action ◽  
Biological Systems ◽  
Molecular Targets ◽  
Pharmacological Action ◽  
Trypanothione Reductase ◽  
Parasitic Disease ◽  
First Line ◽  
Pentavalent Antimony

AbstractAntimonial drugs have been used for a century in the therapy of the parasitic disease leishmaniasis. Even though pentavalent antimonials are still first-line drugs, they exhibit several limitations, including severe side effects, the need for daily parenteral administration and drug resistance. The molecular structure of pentavalent antimonials, their metabolism and mechanism of action, are still being investigated. Previous studies suggest that pentavalent antimony acts as a prodrug which is converted to the active and more toxic trivalent antimony. Other works support the direct involvement of pentavalent antimony. Recent data indicate that thiols and ribose-containing biomolecules may mediate the pharmacological action of these drugs. Trypanothione reductase and zinc-finger proteins were identified as possible molecular targets. This review summarizes the progress achieved to date on the chemistry of antimonial drugs in biological systems.

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