scholarly journals Amikacin potentiator activity of zinc complexed to a pyrithione derivative with enhanced solubility

2022 ◽  
Vol 12 (1) ◽  
Author(s):  
Jesus Magallon ◽  
Peter Vu ◽  
Craig Reeves ◽  
Stella Kwan ◽  
Kimberly Phan ◽  
...  
Keyword(s):  
Growth Inhibition ◽  
Water Solubility ◽  
Target Location ◽  
Enzymatic Reactions ◽  
Enhanced Solubility ◽  
Acetyl Group ◽  
Effective Use ◽  
Time Kill ◽  
Derivatives Of

AbstractResistance to amikacin in Gram-negatives is usually mediated by the 6'-N-acetyltransferase type Ib [AAC(6')-Ib], which catalyzes the transfer of an acetyl group from acetyl CoA to the 6' position of the antibiotic molecule. A path to continue the effective use of amikacin against resistant infections is to combine it with inhibitors of the inactivating reaction. We have recently observed that addition of Zn2+ to in-vitro enzymatic reactions, obliterates acetylation of the acceptor antibiotic. Furthermore, when added to amikacin-containing culture medium in complex to ionophores such as pyrithione (ZnPT), it prevents the growth of resistant strains. An undesired property of ZnPT is its poor water-solubility, a problem that currently affects a large percentage of newly designed drugs. Water-solubility helps drugs to dissolve in body fluids and be transported to the target location. We tested a pyrithione derivative described previously (Magda et al. Cancer Res 68:5318–5325, 2008) that contains the amphoteric group di(ethyleneglycol)-methyl ether at position 5 (compound 5002), a modification that enhances the solubility. Compound 5002 in complex with zinc (Zn5002) was tested to assess growth inhibition of amikacin-resistant Acinetobacter baumannii and Klebsiella pneumoniae strains in the presence of the antibiotic. Zn5002 complexes in combination with amikacin at different concentrations completely inhibited growth of the tested strains. However, the concentrations needed to achieve growth inhibition were higher than those required to achieve the same results using ZnPT. Time-kill assays showed that the effect of the combination amikacin/Zn5002 was bactericidal. These results indicate that derivatives of pyrithione with enhanced water-solubility, a property that would make them drugs with better bioavailability and absorption, are a viable option for designing inhibitors of the resistance to amikacin mediated by AAC(6')-Ib, an enzyme commonly found in the clinics.

scholarly journals Amikacin potentiator activity of zinc complexed to a pyrithione derivative with enhanced solubility

2021 ◽  
Author(s):  
Jesus Magallon ◽  
Peter Vu ◽  
Craig Reeves ◽  
Stella Kwan ◽  
Kimberly Phan ◽  
...  
Keyword(s):  
Growth Inhibition ◽  
Water Solubility ◽  
Target Location ◽  
Enzymatic Reactions ◽  
Enhanced Solubility ◽  
Acetyl Group ◽  
Effective Use ◽  
Time Kill ◽  
Derivatives Of

Resistance to amikacin in Gram-negatives is usually mediated by the 6'-N-acetyltransferase type Ib [AAC(6')-Ib], which catalyzes the transfer of an acetyl group from acetyl CoA to the 6' position of the antibiotic molecule. A path to continue the effective use of amikacin against resistant infections is to combine it with inhibitors of the inactivating reaction. We have recently observed that addition of Zn2+ to in-vitro enzymatic reactions, obliterates acetylation of the acceptor antibiotic. Furthermore, when added to amikacin-containing culture medium in complex to ionophores such as pyrithione (ZnPT), it prevents the growth of resistant strains. An undesired property of ZnPT is its poor water-solubility, a problem that currently affects a large percentage of newly designed drugs. Water-solubility helps drugs to dissolve in body fluids and be transported to the target location. We tested a pyrithione derivative described previously (Magda et al. Cancer Res. 2008, 68:5318-5325) that contains the amphoteric group di(ethyleneglycol)-methyl ether at position 5 (compound 5002), a modification that enhances the solubility. Compound 5002 in complex with zinc (Zn5002) was tested to assess growth inhibition of amikacin-resistant Acinetobacter baumannii and Klebsiella pneumoniae strains in the presence of the antibiotic. Zn5002 complexes in combination with amikacin at different concentrations completely inhibited growth of the tested strains. However, the concentrations needed to achieve growth inhibition were higher than those required to achieve the same results using ZnPT. Time-kill assays showed that the effect of the combination amikacin/Zn5002 was bactericidal. These results indicate that derivatives of pyrithione with enhanced water-solubility, a property that would make them drugs with better bioavailability and absorption, are a viable option for designing inhibitors of the resistance to amikacin mediated by AAC(6')-Ib, an enzyme commonly found in the clinics.

scholarly journals In vitro synergy of 5-nitrofurans, vancomycin and sodium deoxycholate against Gram-negative pathogens

2021 ◽  
Author(s):  
Catrina Olivera ◽  
Vuong Van Hung Le ◽  
Catherine Davenport ◽  
Jasna Rakonjac
Keyword(s):  
Growth Inhibition ◽  
Type Species ◽  
Sodium Deoxycholate ◽  
Gram Positive ◽  
Bacterial Killing ◽  
Gram Negative ◽  
Content Type ◽  
Link Type ◽  
Time Kill

Introduction. There is an urgent need for effective therapies against bacterial infections, especially those caused by antibiotic-resistant Gram-negative pathogens. Hypothesis. Synergistic combinations of existing antimicrobials show promise due to their enhanced efficacies and reduced dosages which can mitigate adverse effects, and therefore can be used as potential antibacterial therapy. Aim. In this study, we sought to characterize the in vitro interaction of 5-nitrofurans, vancomycin and sodium deoxycholate (NVD) against pathogenic bacteria. Methodology. The synergy of the NVD combination was investigated in terms of growth inhibition and bacterial killing using checkerboard and time-kill assays, respectively. Results. Using a three-dimensional checkerboard assay, we showed that 5-nitrofurans, sodium deoxycholate and vancomycin interact synergistically in the growth inhibition of 15 out of 20 Gram-negative strains tested, including clinically significant pathogens such as carbapenemase-producing Escherichia coli , Klebsiella pneumoniae and Acinetobacter baumannii , and interact indifferently against the Gram-positive strains tested. The time-kill assay further confirmed that the triple combination was bactericidal in a synergistic manner. Conclusion. This study demonstrates the synergistic effect of 5-nitrofurans, sodium deoxycholate and vancomycin against Gram-negative pathogens and highlights the potential of the combination as a treatment for Gram-negative and Gram-positive infections.

scholarly journals Two Novel Palbociclib-Resorcinol and Palbociclib-Orcinol Cocrystals with Enhanced Solubility and Dissolution Rate

Pharmaceutics ◽  
2021 ◽  
Vol 14 (1) ◽  
pp. 23
Author(s):  
Chenxin Duan ◽  
Wenwen Liu ◽  
Yunwen Tao ◽  
Feifei Liang ◽  
Yanming Chen ◽  
...  
Keyword(s):  
Water Solubility ◽  
Cancer Drug ◽  
X Ray Diffraction ◽  
Scanning Calorimetry ◽  
Dissolution Rates ◽  
Intrinsic Dissolution ◽  
X Ray ◽  
Enhanced Solubility

Palbociclib (PAL) is an effective anti-breast cancer drug, but its use has been partly restricted due to poor bioavailability (resulting from extremely low water solubility) and serious adverse reactions. In this study, two cocrystals of PAL with resorcinol (RES) or orcinol (ORC) were prepared by evaporation crystallization to enhance their solubility. The cocrystals were characterized by single crystal X-ray diffraction, Hirshfeld surface analysis, powder X-ray diffraction, differential scanning calorimetry, thermogravimetric analysis, Fourier transform infrared and scanning electron microscopy. The intrinsic dissolution rates of the PAL cocrystals were determined in three different dissolution media (pH 1.0, pH 4.5 and pH 6.8), and both cocrystals showed improved dissolution rates at pH 1.0 and pH 6.8 in comparison to the parent drug. In addition, the cocrystals increased the solubility of PAL at pH 6.8 by 2–3 times and showed good stabilities in both the accelerated stability testing and stress testing. The PAL-RES cocrystal also exhibited an improved relative bioavailability (1.24 times) than PAL in vivo pharmacokinetics in rats. Moreover, the in vitro cytotoxicity assay of PAL-RES showed an increased IC50 value for normal cells, suggesting a better biosafety profile than PAL. Co-crystallization may represent a promising strategy for improving the physicochemical properties of PAL with better pharmacokinetics.

Norcantharidin analogues — Synthesis and evaluation of growth inhibition in a panel of selected tumor-cell lines

2007 ◽  
Vol 85 (11) ◽  
pp. 938-944 ◽  
Author(s):  
Liping Deng ◽  
Li Shen ◽  
Jing Zhang ◽  
Bo Yang ◽  
Qiaojun He ◽  
...  
Keyword(s):  
Tumor Cell ◽  
Growth Inhibition ◽  
Cell Lines ◽  
Antiproliferative Activity ◽  
Aromatic Amines ◽  
Cycloaddition Reaction ◽  
Dipolar Cycloaddition ◽  
Tumor Cell Lines ◽  
Derivatives Of

A series of norcantharidin (NCTD) analogues have been synthesized by [3+2]1,3-dipolar cycloaddition reaction of norcantharidin derivatives of substituted aromatic amines with four nitrile oximes. All analogues have been screened for their antiproliferative activity in vitro against a panel of tumor cell lines: KB, SGC-7901, HL60, Bel-7402, HO-8910, and ECA109, producing IC50 values from 0.36 µmol/L to >100 µmol/L. Compound 9d showed potency for the treatment of hepatoma, with IC50 value to Bel-7402 cell line comparable to that of norcantharidin.Key words: norcantharidin analogues, isoxazoline, growth inhibition.

scholarly journals Silver Nanoparticles and Polyphenol Inclusion Compounds Composites for Phytophthora cinnamomi Mycelial Growth Inhibition

Antibiotics ◽  
2018 ◽  
Vol 7 (3) ◽  
pp. 76 ◽  
Author(s):  
Petruta Matei ◽  
Jesús Martín-Gil ◽  
Beatrice Michaela Iacomi ◽  
Eduardo Pérez-Lebeña ◽  
María Barrio-Arredondo ◽  
...  
Keyword(s):  
Silver Nanoparticles ◽  
Growth Inhibition ◽  
Inclusion Compounds ◽  
Mycelial Growth ◽  
Water Solubility ◽  
Phytophthora Cinnamomi ◽  
Deep Eutectic Solvent ◽  
Phase System ◽  
Two Phase

Phytophthora cinnamomi, responsible for “root rot” or “dieback” plant disease, causes a significant amount of economic and environmental impact. In this work, the fungicide action of nanocomposites based on silver nanoparticles and polyphenol inclusion compounds, which feature enhanced bioavailability and water solubility, was assayed for the control of this soil-borne water mold. Inclusion compounds were prepared by an aqueous two-phase system separation method through extraction, either in an hydroalcoholic solution with chitosan oligomers (COS) or in a choline chloride:urea:glycerol deep eutectic solvent (DES). The new inclusion compounds were synthesized from stevioside and various polyphenols (gallic acid, silymarin, ferulic acid and curcumin), in a [6:1] ratio in the COS medium and in a [3:1] ratio in the DES medium, respectively. Their in vitro response against Phytophthora cinnamomi isolate MYC43 (at concentrations of 125, 250 and 500 µg·mL−1) was tested, which found a significant mycelial growth inhibition, particularly high for the composites prepared using DES. Therefore, these nanocomposites hold promise as an alternative to fosetyl-Al and metalaxyl conventional systemic fungicides.

scholarly journals In vitro activities of an investigational quinolone, glycylcycline, glycopeptide, streptogramin, and oxazolidinone tested alone and in combinations against vancomycin-resistant Enterococcus faecium.

1997 ◽  
Vol 41 (11) ◽  
pp. 2573-2575 ◽  
Author(s):  
R C Mercier ◽  
S R Penzak ◽  
M J Rybak
Keyword(s):  
Growth Inhibition ◽  
Active Treatment ◽  
Enterococcus Faecium ◽  
Vancomycin Resistant Enterococcus ◽  
Bacterial Inoculum ◽  
Vancomycin Resistant ◽  
Kill Curve ◽  
Time Kill

We evaluated the in vitro activities of clinafloxacin, CL331,002, LY333328, quinupristin dalfopristin, and eperezolid (formerly known as U-100,592) against four strains of enterococci. All regimens tested resulted in the growth inhibition of each isolate. Against the three clinafloxacin-susceptible strains, clinafloxacin tested alone was the most active treatment, decreasing the bacterial inoculum by more than 3 log10 CFU/ml after 24 h in time-kill curve studies.

scholarly journals In vitro activities of ciprofloxacin and rifampin alone and in combination against growing and nongrowing strains of methicillin-susceptible and methicillin-resistant Staphylococcus aureus.

1997 ◽  
Vol 41 (6) ◽  
pp. 1293-1297 ◽  
Author(s):  
D Bahl ◽  
D A Miller ◽  
I Leviton ◽  
P Gialanella ◽  
M J Wolin ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Drug Interaction ◽  
Growth Inhibition ◽  
Methicillin Resistant Staphylococcus Aureus ◽  
Bactericidal Effect ◽  
Drug Combinations ◽  
Bactericidal Effects ◽  
Time Kill ◽  
Phosphate Buffered Saline

We characterized the effects of ciprofloxacin and rifampin alone and in combination on Staphylococcus aureus in vitro. The effects of drug combinations (e.g., indifferent, antagonistic, or additive interactions) on growth inhibition were compared by disk approximation studies and by determining the fractional inhibitory concentrations. Bactericidal effects in log-phase bacteria and in nongrowing isolates were characterized by time-kill methods. The effect of drug combinations was dependent upon whether or not cells were growing and whether killing or growth inhibition was the endpoint used to measure drug interaction. Despite bactericidal antagonism in time-kill experiments, our in vitro studies suggest several possible explanations for the observed benefits in patients treated with a combination of ciprofloxacin and rifampin for deep-seated staphylococcal infections. Notably, when growth inhibition rather than killing was used to characterize drug interaction, indifference rather than antagonism was observed. An additive bactericidal effect was observed in nongrowing bacteria suspended in phosphate-buffered saline. While rifampin antagonized the bactericidal effects of ciprofloxacin, ciprofloxacin did not antagonize the bactericidal effects of rifampin. Each antimicrobial prevented the emergence of subpopulations that were resistant to the other.

scholarly journals Synergistic Antimicrobial Activities of Folic Acid Antagonists and Nucleoside Analogs

2009 ◽  
Vol 54 (3) ◽  
pp. 1226-1231 ◽  
Author(s):  
Johannes Zander ◽  
Silke Besier ◽  
Hanns Ackermann ◽  
Thomas A. Wichelhaus
Keyword(s):  
Folic Acid ◽  
Nucleoside Analogs ◽  
Bactericidal Effect ◽  
Antimicrobial Activities ◽  
Nucleoside Analog ◽  
Folic Acid Antagonists ◽  
Bacterial Utilization ◽  
Time Kill ◽  
Derivatives Of

ABSTRACT The antimicrobial activities of folic acid antagonists are supposed to be antagonized by elevated extracellular thymidine concentrations in damaged host tissues. Therefore, this study was aimed at screening for nucleoside analogs that impair bacterial thymidine utilization and analyzing the combined antimicrobial activities of nucleoside analogs and folic acid antagonists in the presence of thymidine. Our screening results revealed that different nucleoside analogs, in particular halogenated derivatives of 2′-deoxyuridine, substantially impaired the bacterial utilization of extracellular thymidine in Staphylococcus aureus. Time-kill methods showed that 5-iodo-2′-deoxyuridine enhanced the extent of killing of trimethoprim-sulfamethoxazole (SXT) at 24 h against S. aureus in the presence of thymidine (200 μg/liter). While SXT (40 mg/liter) alone did not kill bacteria in the presence of thymidine, its combination with the nucleoside analog at a concentration of 8 μmol/liter showed a bactericidal effect. Moreover, 5-iodo-2′-deoxyuridine combined with SXT in the presence of thymidine showed a broad spectrum of activity against several Gram-positive and Gram-negative bacteria. In conclusion, these data provide evidence that the in vitro antimicrobial activity of SXT in the presence of thymidine can be significantly improved by combination with a nucleoside analog.

scholarly journals In Vitro Interactions of Micafungin with Amphotericin B against Clinical Isolates of Candida spp.

2008 ◽  
Vol 52 (4) ◽  
pp. 1529-1532 ◽  
Author(s):  
Carolina Serena ◽  
Marçal Mariné ◽  
Guillermo Quindós ◽  
Alfonso J. Carrillo ◽  
J. F. Cano ◽  
...  
Keyword(s):  
Growth Inhibition ◽  
Amphotericin B ◽  
Drug Concentration ◽  
Vitro Activity ◽  
In Vitro Activity ◽  
Candida Spp ◽  
Synergistic Interactions ◽  
Time Kill ◽  
In Vitro Interactions

ABSTRACT The in vitro activity of amphotericin B in combination with micafungin was evaluated against 115 isolates representing seven species of Candida. Overall, the percentages of synergistic interactions were 50% and 20% when the MIC-2 (lowest drug concentration to cause a prominent reduction in growth) and MIC-0 (lowest drug concentration to cause 100% growth inhibition) end point criteria, respectively, were used. Antagonism was not observed. Some of the interactions were confirmed by time-kill assays.

scholarly journals Synthesis, physicochemical characterization and antibacterial activity of novel (benzoylamino)methyl derivatives of quinolones

2016 ◽  
Vol 35 (2) ◽  
pp. 179 ◽  
Author(s):  
Pranvera Breznica-Selmani ◽  
Kristina Mladenovska ◽  
Gerald Dräger ◽  
Bozhana Mikhova ◽  
Nikola Panovski ◽  
...  
Keyword(s):  
Water Solubility ◽  
Physicochemical Characterization ◽  
2D Nmr ◽  
Antimicrobial Activities ◽  
Distribution Coefficients ◽  
Bacterial Cells ◽  
Methyl Derivatives ◽  
Leading Compounds ◽  
Derivatives Of

Herein we report the synthesis of different derivatives of (fluoro)quinolones norfloxacin, ciprofloxacin and pipemidic acid, by incorporating (benzoylamino)methyl on the free nitrogen of the pyperazinyl moiety. The compounds were structurally characterized by 1D and 2D NMR, FTIR and high-resolution mass spectroscopy. In addition, their physicochemical properties were a matter of interest to be correlated with their structure and antimicrobial activity<em> in vitro</em>. Their antimicrobial activities were screened against Gram-positive, Gram-negative bacteria and <em>C. albicans</em>. Higher distribution coefficients and consequently lower water solubility were determined for all synthesized compounds than the ones of the corresponding leading compounds. Inconsequential correlations between the lipophilicity of the compounds and MIC were observed, suggesting that passive diffusion is not the only mechanism for their penetration into bacterial cells. Further studies are needed to determine how substitutions in the (fluoro)quinolone moiety affect the primary target(s), substrate behavior in respect to bacterial transporters and overall bioavailability.

Sign in / Sign up

Export Citation Format

Share Document