Self-immolative polymers with potent and selective antibacterial activity by hydrophilic side chain grafting

2018 ◽  
Vol 6 (44) ◽  
pp. 7217-7229 ◽  
Author(s):  
Cansu Ergene ◽  
Edmund F. Palermo
Keyword(s):  
Antibacterial Activity ◽  
Red Blood Cells ◽  
Small Molecules ◽  
Blood Cells ◽  
Side Chain ◽  
Chemical Stimulus ◽  
Hemolytic Toxicity

Self-immolative polymers, which exert potent antibacterial activity with low hemolytic toxicity to red blood cells, are triggered to unzip into small molecules by a chemical stimulus.

scholarly journals Physicochemical and Structural Parameters Contributing to the Antibacterial Activity and Efflux Susceptibility of Small Molecule Inhibitors of Escherichia coli

2021 ◽  
Author(s):  
Sara S. El Zahed ◽  
Shawn French ◽  
Maya A. Farha ◽  
Garima Kumar ◽  
Eric D. Brown
Keyword(s):  
Machine Learning ◽  
Escherichia Coli ◽  
Antibacterial Activity ◽  
Small Molecules ◽  
Small Molecule ◽  
In Silico ◽  
Molecular Descriptors ◽  
Structural Parameters ◽  
Side Chain ◽  
Gram Negative

Discovering new Gram-negative antibiotics has been a challenge for decades. This has been largely attributed to a limited understanding of the molecular descriptors governing Gram-negative permeation and efflux evasion. Herein, we address the contribution of efflux using a novel approach that applies multivariate analysis, machine learning, and structure-based clustering to some 4,500 actives from a small molecule screen in efflux-compromised Escherichia coli. We employed principal-component analysis and trained two decision tree-based machine learning models to investigate descriptors contributing to the antibacterial activity and efflux susceptibility of these actives. This approach revealed that the Gram-negative activity of hydrophobic and planar small molecules with low molecular stability is limited to efflux-compromised E. coli. Further, molecules with reduced branching and compactness showed increased susceptibility to efflux. Given these distinct properties that govern efflux, we developed the first machine learning model, called Susceptibility to Efflux Random Forest (SERF), as a tool to analyze the molecular descriptors of small molecules and predict those that could be susceptible to efflux pumps in silico. Here, SERF demonstrated high accuracy in identifying such molecules. Further, we clustered all 4,500 actives based on their core structures and identified distinct clusters highlighting side chain moieties that cause marked changes in efflux susceptibility. In all, our work reveals a role for physicochemical and structural parameters in governing efflux, presents a machine learning tool for rapid in silico analysis of efflux susceptibility, and provides a proof of principle for the potential of exploiting side chain modification to design novel antimicrobials evading efflux pumps.

Antibacterial Activity of Hydrolyzed Red Blood Cells in Vitro

1950 ◽  
Vol 74 (2) ◽  
pp. 346-350 ◽  
Author(s):  
D. M. Whitney ◽  
L. Anigstein ◽  
D. W. Micks
Keyword(s):  
Antibacterial Activity ◽  
Red Blood Cells ◽  
Blood Cells

scholarly journals A Specific Point Mutant at Position 1 of the Influenza Hemagglutinin Fusion Peptide Displays a Hemifusion Phenotype

1999 ◽  
Vol 10 (8) ◽  
pp. 2759-2769 ◽  
Author(s):  
Hui Qiao ◽  
R. Todd Armstrong ◽  
Grigory B. Melikyan ◽  
Fredric S. Cohen ◽  
Judith M. White
Keyword(s):  
Red Blood Cells ◽  
Blood Cells ◽  
Antigenic Site ◽  
Fusion Peptide ◽  
Side Chain ◽  
Fusion Activity ◽  
Second Stage ◽  
Influenza Hemagglutinin ◽  
Electrophysiological Studies ◽  
Surprising Finding

We showed previously that substitution of the first residue of the influenza hemagglutinin (HA) fusion peptide Gly1 with Glu abolishes fusion activity. In the present study we asked whether this striking phenotype was due to the charge or side-chain volume of the substituted Glu. To do this we generated and characterized six mutants with substitutions at position 1: Gly1 to Ala, Ser, Val, Glu, Gln, or Lys. We found the following. All mutants were expressed at the cell surface, could be cleaved from the precursor (HA0) to the fusion permissive form (HA1-S-S-HA2), bound antibodies against the major antigenic site, bound red blood cells, and changed conformation at low pH. Only Gly, Ala, and Ser supported lipid mixing during fusion with red blood cells. Only Gly and Ala supported content mixing. Ser HA, therefore, displayed a hemifusion phenotype. The hemifusion phenotype of Ser HA was confirmed by electrophysiological studies. Our findings indicate that the first residue of the HA fusion peptide must be small (e.g., Gly, Ala, or Ser) to promote lipid mixing and must be small and apolar (e.g., Gly or Ala) to support both lipid and content mixing. The finding that Val HA displays no fusion activity underscores the idea that hydrophobicity is not the sole factor dictating fusion peptide function. The surprising finding that Ser HA displays hemifusion suggests that the HA ectodomain functions not only in the first stage of fusion, lipid mixing, but also, either directly or indirectly, in the second stage of fusion, content mixing.

scholarly journals ГЕМАТОЛОГІЧНІ ТА МІКРОБІОЛОГІЧНІ ПОКАЗНИКИ, СТАН ПРИРОДНИХ МЕХАНІЗМІВ ЗАХИСТУ У КОРОПА ЗА ДІЇ ПРЕПАРАТУ «ФЛЮМЕК»

2016 ◽  
Vol 18 (3(71)) ◽  
pp. 100-104
Author(s):  
H. Solopova ◽  
O. Vishchur
Keyword(s):  
Antibacterial Activity ◽  
Red Blood Cells ◽  
Bactericidal Activity ◽  
Immune Complexes ◽  
Blood Cells ◽  
Hemoglobin Concentration ◽  
Circulating Immune Complexes ◽  
Antibacterial Drug ◽  
High Antibacterial Activity ◽  
The Impact

In the article presented results of own researches on the impact of antibacterial drug «Flyumek» on microbiological, hematological and immunological parameters of fish.The study was conducted in three groups of healthy age–2 carp, it was six animals each groups. The first group – research, through which the probe within 7 days of antibiotic «Flyumek» at 10 mg/kg of fish with 3% starch suspension, the second experimental group – 20 mg/kg of fish, the third group – control, received only 3% in starch suspension. Fish was kept in special trays under conditions of continuous closed system of water circulation. The material for the research served fish blood, which was taken after the experiment.For determine the sensitivity of pathogenic microorganisms of fish to the drug «Flyumek»  was taken biological material from external integument, gills and internal organs (kidneys) carp with signs of the most common infectious diseases – Aeromonas infection. It was found a high antibacterial activity of the drug – diameter zone growth retardation culture around the disc was 25 mm.Investigated hematological parameters, particularly the number of red blood cells and hemoglobin concentration in the blood of carp experimental and control groups were within standard values for the age and species of fish. Not recorded probable changes in the number of red blood cells and hemoglobin concentration in the blood of experimental carp groups compared to control. This suggests no violation of the oxygen–transport function of red blood cells and hemolysis .Was studied parameters characterizing humoral nonspecific resistance – lysozyme and bactericidal activity of serum and content of circulating immune complexes. Stated that the fish that received study drug in an amount of 10 mg / kg, the content of circulating immune complexes was 51.7 ± 1.78 mmol/l and virtually no different from the control group, where their content – 50.3 ± 1.78 mmol/l, and the application of higher doses – 20 mg/kg, recorded an increase in their level to 60.3 ± 2.16 mmol/l, indicating a tendency to increase the antigenic load on the carp body . As a result dose of the drug «Flyumek» 10 mg/kg caused increase lysozyme and serum bactericidal activity of fish according to 10.0 (p < 0.05) and 11.5%. However, the use of larger doses – 20 mg/kg caused a downward trend bactericidal activity, but did not significantly affect the activity lysozyme serum.The results of the research indicate a high antibacterial activity of the drug «Flyumek» and no immunosuppressive action of investigational drug on humoral non–specific resistance of the organism carp. In this case, the drug dose of 10 mg/kg causes immune–stimulating effects on the natural defense mechanisms of fish. 

Hemoglobin crystals of the red blood cells in the human renal cortex: electron microscopic observations of the renal lithiasis

1978 ◽  
Vol 36 (2) ◽  
pp. 480-481
Author(s):  
Kosuke Ueda ◽  
Hiroto Washida ◽  
Nakazo Watari
Keyword(s):  
Red Blood Cells ◽  
Blood Cells ◽  
Renal Cortex ◽  
Uranyl Acetate ◽  
Osmic Acid ◽  
Renal Lithiasis ◽  
Electron Microscopic ◽  
Hemoglobin C ◽  
First Case ◽  
Ultrathin Sections

IntroductionHemoglobin crystals in the red blood cells were electronmicroscopically reported by Fawcett in the cat myocardium. In the human, Lessin revealed crystal-containing cells in the periphral blood of hemoglobin C disease patients. We found the hemoglobin crystals and its agglutination in the erythrocytes in the renal cortex of the human renal lithiasis, and these patients had no hematological abnormalities or other diseases out of the renal lithiasis. Hemoglobin crystals in the human erythrocytes were confirmed to be the first case in the kidney.Material and MethodsTen cases of the human renal biopsies were performed on the operations of the seven pyelolithotomies and three ureterolithotomies. The each specimens were primarily fixed in cacodylate buffered 3. 0% glutaraldehyde and post fixed in osmic acid, dehydrated in graded concentrations of ethanol, and then embedded in Epon 812. Ultrathin sections, cut on LKB microtome, were doubly stained with uranyl acetate and lead citrate.

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