scholarly journals ABC-F Proteins Mediate Antibiotic Resistance through Ribosomal Protection

mBio ◽  
2016 ◽  
Vol 7 (2) ◽  
Author(s):  
Liam K. R. Sharkey ◽  
Thomas A. Edwards ◽  
Alex J. O’Neill
Keyword(s):  
Antibiotic Resistance ◽  
Direct Evidence ◽  
New Drugs ◽  
Bacterial Ribosome ◽  
Broad Array ◽  
Clinically Significant ◽  
Antibiotic Efflux ◽  
Dose Dependent ◽  
Ribosomal Protection

ABSTRACTMembers of the ABC-F subfamily of ATP-binding cassette proteins mediate resistance to a broad array of clinically important antibiotic classes that target the ribosome of Gram-positive pathogens. The mechanism by which these proteins act has been a subject of long-standing controversy, with two competing hypotheses each having gained considerable support: antibiotic efflux versus ribosomal protection. Here, we report on studies employing a combination of bacteriological and biochemical techniques to unravel the mechanism of resistance of these proteins, and provide several lines of evidence that together offer clear support to the ribosomal protection hypothesis. Of particular note, we show that addition of purified ABC-F proteins to anin vitrotranslation assay prompts dose-dependent rescue of translation, and demonstrate that such proteins are capable of displacing antibiotic from the ribosomein vitro. To our knowledge, these experiments constitute the first direct evidence that ABC-F proteins mediate antibiotic resistance through ribosomal protection.IMPORTANCEAntimicrobial resistance ranks among the greatest threats currently facing human health. Elucidation of the mechanisms by which microorganisms resist the effect of antibiotics is central to understanding the biology of this phenomenon and has the potential to inform the development of new drugs capable of blocking or circumventing resistance. Members of the ABC-F family, which includelsa(A),msr(A),optr(A), andvga(A), collectively yield resistance to a broader range of clinically significant antibiotic classes than any other family of resistance determinants, although their mechanism of action has been controversial since their discovery 25 years ago. Here we present the first direct evidence that proteins of the ABC-F family act to protect the bacterial ribosome from antibiotic-mediated inhibition.

Medicinal Au(i) compounds targeting urease as prospective antimicrobial agents: unveiling the structural basis for enzyme inhibition

2021 ◽  
Author(s):  
Luca Mazzei ◽  
Lara Massai ◽  
Michele Cianci ◽  
Luigi Messori ◽  
Stefano Ciurli
Keyword(s):  
Antibiotic Resistance ◽  
Enzyme Inhibition ◽  
Antimicrobial Agents ◽  
Antimicrobial Properties ◽  
New Drugs ◽  
Structural Basis ◽  
Great Promise ◽  
Gold Compounds

A few gold compounds were recently found to show antimicrobial properties in vitro, holding great promise for the discovery of new drugs to overcome antibiotic resistance.

scholarly journals In Vitro and In Vivo Antifungal Activities of T-2307, a Novel Arylamidine

2008 ◽  
Vol 52 (4) ◽  
pp. 1318-1324 ◽  
Author(s):  
Junichi Mitsuyama ◽  
Nobuhiko Nomura ◽  
Kyoko Hashimoto ◽  
Eio Yamada ◽  
Hiroshi Nishikawa ◽  
...  
Keyword(s):  
Cryptococcus Neoformans ◽  
Amphotericin B ◽  
Antifungal Activities ◽  
Spectrum Activity ◽  
Effective Doses ◽  
Fluconazole Resistant ◽  
Clinically Significant ◽  
Dose Dependent

ABSTRACT The in vitro and in vivo antifungal activities of T-2307, a novel arylamidine, were evaluated and compared with those of fluconazole, voriconazole, micafungin, and amphotericin B. T-2307 exhibited broad-spectrum activity against clinically significant pathogens, including Candida species (MIC range, 0.00025 to 0.0078 μg/ml), Cryptococcus neoformans (MIC range, 0.0039 to 0.0625 μg/ml), and Aspergillus species (MIC range, 0.0156 to 4 μg/ml). Furthermore, T-2307 exhibited potent activity against fluconazole-resistant and fluconazole-susceptible-dose-dependent Candida albicans strains as well as against azole-susceptible strains. T-2307 exhibited fungicidal activity against some Candida and Aspergillus species and against Cryptococcus neoformans. In mouse models of disseminated candidiasis, cryptococcosis, and aspergillosis, the 50% effective doses of T-2307 were 0.00755, 0.117, and 0.391 mg·kg−1·dose−1, respectively. This agent was considerably more active than micafungin and amphotericin B against candidiasis and than amphotericin B against cryptococcosis, and its activity was comparable to the activities of micafungin and amphotericin B against aspergillosis. The results of preclinical in vitro and in vivo evaluations performed thus far indicate that T-2307 could represent a potent injectable agent for the treatment of candidiasis, cryptococcosis, and aspergillosis.

Effect of Ultra-Small Chitosan Nanoparticles Doped with Brimonidine on the Ultra-Structure of the Trabecular Meshwork of Glaucoma Patients

2019 ◽  
Vol 25 (6) ◽  
pp. 1352-1366 ◽  
Author(s):  
Indu Barwal ◽  
Rahul Kumar ◽  
Tanuj Dada ◽  
Subhash Chandra Yadav
Keyword(s):  
Trabecular Meshwork ◽  
Direct Evidence ◽  
Storage Stability ◽  
Drug Loading ◽  
Chitosan Nanoparticles ◽  
Topical Administration ◽  
Loading Capacity ◽  
Adrenergic Agonist ◽  
Dose Dependent

AbstractBrimonidine, an anti-glaucoma medicine, acts as an adrenergic agonist which decreases the synthesis of aqueous humour and increases the amount of drainage through Schlemm's canal and trabecular meshwork, but shows dose-dependent (0.2% solution thrice daily) toxicity. To reduce the side effects and improve the efficacy, brimonidine was nanoencapsulated on ultra-small-sized chitosan nanoparticles (nanobrimonidine) (28 ± 4 nm) with 39% encapsulation efficiency, monodispersity, freeze–thawing capability, storage stability, and 2% drug loading capacity. This nanocomplex showed burst, half, and complete release at 0.5, 45, and 100 h, respectively. Nanobrimonidine did not show any in vitro toxicity and was taken up by caveolae-mediated endocytosis. The nanobrimonidine-treated trabeculectomy tissue of glaucoma patients showed better dilation of the trabecular meshwork under the electron microscope. This is direct evidence for better bioavailability of nanobrimonidine after topical administration. Thus, the developed nanobrimonidine has the potential to improve the efficacy, reduce dosage and frequency, and improve delivery to the anterior chamber of the eye.

scholarly journals Susceptibility testing of Candida glabrata clinical strains to echinocandins using SensititreTM YeastOneTM system

2018 ◽  
Vol 20 (1) ◽  
pp. 49-54 ◽  
Author(s):  
Alexander V. Veselov ◽  
N.V. Vasilyeva ◽  
T.S. Bogomolova ◽  
E.R. Raush ◽  
O.Yu. Kutsevalova ◽  
...  
Keyword(s):  
Susceptibility Testing ◽  
Venous Catheter ◽  
Minimal Inhibitory Concentrations ◽  
Long Term Trends ◽  
Resistant Strains ◽  
Clinically Significant ◽  
Susceptibility Profiles ◽  
Dose Dependent

Objective. To determine susceptibility of C. glabrata isolates to anidulafungin, caspofungin and micafungin using the SensititreTM YeastOneTM system. Materials and Methods. C. glabrata isolates were taken prospectively from clinical specimens or from strains collections in the participating sites. Susceptibility determination was performed using SensititreTM YeastOneTM (YO10 panel) according to the manufacturer’s guidance, and results were interpreted with M27-A3 CLSI guidelines. Susceptibility of C. glabrata to fluconazole was also determined in order to assess possible correlations of echinocandins and fluconazole minimal inhibitory concentrations (MICs) in resistant strains. Results. A total of 59 C. glabrata strains were tested. The strains were isolated mostly from peripheral blood (44%). Among clinically significant medical conditions/risk factors and co-morbidities, central venous catheter, solid tumors, and abdominal surgery were identified in 20 (33.9%), 19 (32.2%), and 14 (23.7%) patients, respectively. Most MIC values of echinocandins were 0.015 and 0.03 mg/L. Caspofungin has slightly higher MIC values than those of anidulafungin and micafungin. No isolates were resistant to any of the echinocandins. The only 2 patients were receiving echinocandin therapy at the time of taking biosamples (with no reported information about treatment efficacy); those strains were also susceptible to all echinocandins. All C. glabrata strains were susceptible dose-dependent to fluconazole with MIC values between 2 and 32 mg/L. Conclusions. All of the echinocandins have a high and comparable in vitro activity against C. glabrata, including strains which are susceptible dose-depended to fluconazole. More prospective studies are needed to investigate the long-term trends in susceptibility profiles of pathogens causing candidiasis, especially C. glabrata.

scholarly journals In vitro activities of cellulase and ceftazidime, alone and in combination against Pseudomonas aeruginosa biofilms

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Esmat Kamali ◽  
Ailar Jamali ◽  
Ahdieh Izanloo ◽  
Abdollah Ardebili
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Antibiotic Resistance ◽  
Biofilm Formation ◽  
Glycoside Hydrolase ◽  
Dependent Manner ◽  
Wound Infections ◽  
Persistent Infections ◽  
Novel Strategy ◽  
Dose Dependent

Abstract Background Biofilms are a main pathogenicity feature of Pseudomonas aeruginosa and has a significant role in antibiotic resistance and persistent infections in humans. We investigated the in vitro activities of antibiotic ceftazidime and enzyme cellulase, either alone or in combination against biofilms of P. aeruginosa. Results Both ceftazidime and cellulase significantly decreased biofilm formation in all strains in a dose-dependent manner. Combination of enzyme at concentrations of 1.25, 2.5, 5, and 10 U/mL tested with 1/16× MIC of antibiotic led to a significant reduction in biofilm biomass. Cellulase showed a significant detachment effect on biofilms at three concentrations of 10 U/mL, 5 U/mL, and 2.5 U/mL. The MIC, MBC, and MBEC values of ceftazidime were 2 to 4 µg/mL, 4 to 8 µg/mL, and 2048 to 8192 µg/mL. When combined with cellulase, the MBECs of antibiotic showed a significant decrease from 32- to 128-fold. Conclusions Combination of the ceftazidime and the cellulase had significant anti-biofilm effects, including inhibition of biofilm formation and biofilm eradication in P. aeruginosa. These data suggest that glycoside hydrolase therapy as a novel strategy has the potential to enhance the efficacy of antibiotics and helps to resolve biofilm-associated wound infections caused by this pathogen.

scholarly journals Efficacy of CS-758, a Novel Triazole, against Experimental Fluconazole-Resistant Oropharyngeal Candidiasis in Mice

2003 ◽  
Vol 47 (2) ◽  
pp. 601-606 ◽  
Author(s):  
Yasuki Kamai ◽  
Mikie Kubota ◽  
Takashi Fukuoka ◽  
Yoko Kamai ◽  
Naoyuki Maeda ◽  
...  
Keyword(s):  
Resistant Strain ◽  
Viable Cell ◽  
New Drugs ◽  
Histopathological Study ◽  
Strongly Correlated ◽  
Oropharyngeal Candidiasis ◽  
Cell Counts ◽  
Fluconazole Resistant ◽  
Dose Dependent

ABSTRACT The therapeutic efficacy of CS-758, a novel triazole, was evaluated against experimental murine oropharyngeal candidiasis induced by Candida albicans with various susceptibilities to fluconazole. Against infections induced by strains with various susceptibilities to fluconazole, the efficacy of fluconazole was strongly correlated with the MIC of fluconazole, as measured by the NCCLS method, and agreed with the NCCLS interpretive breakpoints, suggesting that the efficacies of new drugs could be predicted by using this model. The results of the fungal burden study corresponded with the results of the histopathological study. CS-758 exhibited potent in vitro activity (MICs, 0.004 to 0.06 μg/ml) against the strains used in this murine model including fluconazole-susceptible dose-dependent and fluconazole-resistant strains (fluconazole MICs, 16 to 64 μg/ml). CS-758 exhibited excellent efficacy against the infections induced by all the strains including a fluconazole-resistant strain, and the reductions in viable cell counts were significant at 10 and 50 mg/kg of body weight/dose. Fluconazole was not effective even at 50 mg/kg/dose against infections induced by a fluconazole-resistant strain (fluconazole MIC, 64 μg/ml). These results suggest that CS-758 is a promising compound for the treatment of oropharyngeal candidiasis including fluconazole-refractory infections.

scholarly journals In Vitro Evaluation of Lavandula angustifolia Essential Oil on Anti-Toxoplasma Activity

2021 ◽  
Vol 11 ◽  
Author(s):  
Na Yao ◽  
Jia-Kang He ◽  
Ming Pan ◽  
Zhao-Feng Hou ◽  
Jin-Jun Xu ◽  
...  
Keyword(s):  
Essential Oil ◽  
Plaque Assay ◽  
Acute Stage ◽  
New Drugs ◽  
Dependent Manner ◽  
Lavandula Angustifolia ◽  
Low Toxicity ◽  
Parasitic Effect ◽  
Dose Dependent

The current methods of treating toxoplasmosis have a number of side effects, and these therapies are only effective against the acute stage of the disease. Thus, development of new low toxicity and efficient anti-Toxoplasma drugs is extremely important. Natural products are important sources for screening new drugs; among them, essential oils (EOs) have efficacy in anti-bacterial, anti-inflammatory, anti-insect, and other aspects. In this study, 16 EOs were screened for their anti-T. gondii activity. Lavandula angustifolia essential oil (La EO)was found to have an anti-parasitic effect on T. gondii. The cytotoxicity of La EO was firstly evaluated using the MTT assay on human foreskin fibroblast (HFF) cells, and then the anti-T. gondii activity was evaluated by plaque assay. Finally, the invasion experiment and electron microscope observation were used to study the mechanism of La EO in anti-toxoplasma activity. The results indicated that the CC50 of La EO was 4.48 mg/ml and that La EO had activity against T. gondii and the inhibition was in a dose-dependent manner under safe concentrations. La EO was able to reduce T. gondii invasion, which may be due to its detrimental effect on changes of the morphology of tachyzoites. These findings indicated that La EO could be a potential drug for treating toxoplasmosis.

scholarly journals In Vitro Evaluation of Rigosertib Antitumoral and Radiosensitizing Effects against Human Cholangiocarcinoma Cells

2021 ◽  
Vol 22 (15) ◽  
pp. 8230
Author(s):  
Alessio Malacrida ◽  
Roberta Rigolio ◽  
Luigi Celio ◽  
Silvia Damian ◽  
Guido Cavaletti ◽  
...  
Keyword(s):  
Survival Rate ◽  
Kinase Inhibitor ◽  
Therapeutic Option ◽  
New Drugs ◽  
Migration And Invasion ◽  
Dependent Manner ◽  
M Phase ◽  
Nuclear Alterations ◽  
Dose Dependent

Cholangiocarcinoma is the first most common cancer of the biliary tract. To date, surgical resection is the only potentially curative option, but it is possible only for a limited percentage of patients, and in any case survival rate is quite low. Moreover, cholangiocarcinoma is often chemotherapy-resistant, and the only drug with a significant benefit for patient’s survival is Gemcitabine. It is necessary to find new drugs or combination therapies to treat nonresectable cholangiocarcinoma and improve the overall survival rate of patients. In this work, we evaluate in vitro the antitumoral effects of Rigosertib, a multi-kinase inhibitor in clinical development, against cholangiocarcinoma EGI-1 cell lines. Rigosertib impairs EGI-1 cell viability in a dose- and time-dependent manner, reversibility is dose-dependent, and significant morphological and nuclear alterations occur. Moreover, Rigosertib induces the arrest of the cell cycle in the G2/M phase, increases autophagy, and inhibits proteasome, cell migration, and invasion. Lastly, Rigosertib shows to be a stronger radiosensitizer than Gemcitabine and 5-Fluorouracil. In conclusion, Rigosertib could be a potential therapeutic option, alone or in combination with radiations, for nonresectable patients with cholangiocarcinoma.

Increased Protein Synthesis by Human Platelets during Phagocytosis of Latex Particles in Vitro

1976 ◽  
Vol 35 (02) ◽  
pp. 350-357 ◽  
Author(s):  
Hana Bessler ◽  
Galila Agam ◽  
Meir Djaldetti
Keyword(s):  
Protein Synthesis ◽  
Fold Increase ◽  
Human Platelets ◽  
Polystyrene Latex ◽  
Latex Particles ◽  
The Third ◽  
Platelet Protein ◽  
Dose Dependent ◽  
Phagocytotic Activity

SummaryA three-fold increase of protein synthesis by human platelets during in vitro phagocytosis of polystyrene latex particles was detected. During the first two hours of incubation, the percentage of phagocytizing platelets and the number of latex particles per platelet increased; by the end of the third hour, the first parameter remained stable, while the number of latex particles per cell had decreased.Vincristine (20 μg/ml of cell suspension) inhibited platelet protein synthesis. This effect was both time- and dose-dependent. The drug also caused a decrease in the number of phagocytizing cells, as well as in their phagocytotic activity.

The Effect of Adrenaline Infusions on Blood Coagulation in Normal and Haemophilia B Dogs

1966 ◽  
Vol 15 (03/04) ◽  
pp. 349-364 ◽  
Author(s):  
A.H Özge ◽  
H.C Rowsell ◽  
H.G Downie ◽  
J.F Mustard
Keyword(s):  
Body Weight ◽  
Factor Viii ◽  
Factor Ix ◽  
Clotting Factor ◽  
Blood Ph ◽  
Order Of Magnitude ◽  
Dose Dependent ◽  
Generation Test ◽  
Plasma Activity

SummaryThe addition of trace amounts of adrenaline to whole blood in plasma in vitro increased factor VIII, factor IX and whole plasma activity in the thromboplastin generation test. This was dose dependent.Adrenaline infusions less than 22 (μg/kg body weight in normal dogs accelerated clotting, increased factor IX, factor VIII and whole plasma activity in the thromboplastin generation test and caused a fall in blood pH. In a factor IX deficient dog, there was no increase in factor IX activity. After adrenaline infusions, however, the other changes occurred and were of the same order of magnitude as in the normal. Adrenaline in doses greater than 22 μg/kg body weight did not produce as great an effect on clotting in normal or factor IX deficient dogs. The platelet count in the peripheral blood was increased following the infusion of all doses of adrenaline. These observations suggest that the accelerating effect of adrenaline on clotting is not mediated through increase in activity of a specific clotting factor.

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