scholarly journals Antibacterial Activities and Characterization of Novel Inhibitors of LpxC

2002 ◽  
Vol 46 (6) ◽  
pp. 1793-1799 ◽  
Author(s):  
John M. Clements ◽  
Fanny Coignard ◽  
Ian Johnson ◽  
Stephen Chandler ◽  
Shilpa Palan ◽  
...  
Keyword(s):  
Burkholderia Cepacia ◽  
Lipid A ◽  
Antibacterial Activities ◽  
Vitro Assay ◽  
Gram Negative ◽  
E Coli ◽  
Antibacterial Target ◽  
Derivatives Of

ABSTRACT Lipid A is the hydrophobic anchor of lipopolysaccharide (LPS) and forms the major lipid component of the outer monolayer of the outer membrane of gram-negative bacteria. Lipid A is required for bacterial growth and virulence, and inhibition of its biosynthesis is lethal to bacteria. UDP-3-O-(R-3-hydroxymyristoyl)-N-acetylglucosamine deacetylase (LpxC) is a metalloenzyme that catalyzes the second step in the biosynthesis of lipid A. Inhibitors of LpxC have previously been shown to have antibiotic activities. We have screened a metalloenzyme inhibitor library for antibacterial activities against an Escherichia coli strain with reduced LpxC activity. From this screen, a series of sulfonamide derivatives of the α-(R)-amino hydroxamic acids, exemplified by BB-78484 and BB-78485, have been identified as having potent inhibitory activities against LpxC in an in vitro assay. Leads from this series showed gram-negative selective activities against members of the Enterobacteriaceae, Serratia marcescens, Morganella morganii, Haemophilus influenzae, Moraxella catarrhalis, and Burkholderia cepacia. BB-78484 was bactericidal against E. coli, achieving 3-log killing in 4 h at a concentration 4 times above the MIC, as would be predicted for an inhibitor of lipid A biosynthesis. E. coli mutants with decreased susceptibility to BB-78484 were selected. Analysis of these mutants revealed that resistance arose as a consequence of mutations in the fabZ or lpxC genes. These data confirm the antibacterial target of BB-78484 and BB-78485 and validate LpxC as a target for gram-negative selective antibacterials.

scholarly journals A Novel 3-Deoxy-d-manno-Octulosonic Acid (Kdo) Hydrolase That Removes the Outer Kdo Sugar of Helicobacter pylori Lipopolysaccharide

2005 ◽  
Vol 187 (10) ◽  
pp. 3374-3383 ◽  
Author(s):  
Christopher Stead ◽  
An Tran ◽  
Donald Ferguson ◽  
Sara McGrath ◽  
Robert Cotter ◽  
...  
Keyword(s):  
Helicobacter Pylori ◽  
Lipid A ◽  
In Vitro Assay ◽  
Spectrometric Analysis ◽  
Vitro Assay ◽  
The Core ◽  
H Pylori

ABSTRACT The lipid A domain anchors lipopolysaccharide (LPS) to the outer membrane and is typically a disaccharide of glucosamine that is both acylated and phosphorylated. The core and O-antigen carbohydrate domains are linked to the lipid A moiety through the eight-carbon sugar 3-deoxy-d-manno-octulosonic acid known as Kdo. Helicobacter pylori LPS has been characterized as having a single Kdo residue attached to lipid A, predicting in vivo a monofunctional Kdo transferase (WaaA). However, using an in vitro assay system we demonstrate that H. pylori WaaA is a bifunctional enzyme transferring two Kdo sugars to the tetra-acylated lipid A precursor lipid IVA. In the present work we report the discovery of a Kdo hydrolase in membranes of H. pylori capable of removing the outer Kdo sugar from Kdo2-lipid A. Enzymatic removal of the Kdo group was dependent upon prior removal of the 1-phosphate group from the lipid A domain, and mass spectrometric analysis of the reaction product confirmed the enzymatic removal of a single Kdo residue by the Kdo-trimming enzyme. This is the first characterization of a Kdo hydrolase involved in the modification of gram-negative bacterial LPS.

Synthesis and Evaluation of Novel Fluorobenzimidazole Derivatives as Antibacterial and Antifungal Agents

2019 ◽  
Vol 4 (4) ◽  
pp. 209-215
Author(s):  
D. Joshi ◽  
R. Narigara ◽  
G. Jani ◽  
K. Parikh
Keyword(s):  
Bacterial Strains ◽  
Compound I ◽  
Substituted Anilines ◽  
Gram Negative ◽  
E Coli ◽  
New Class ◽  
Antibacterial And Antifungal ◽  
Derivatives Of ◽  
Multiple Step

A new class of fluorobenzimidazole derivatives (IIIa-j)was synthesized to investigate their antimicrobial potential. All the compounds were prepared by multiple step synthesis, initiating from the synthesis of 5-(difluoromethoxy)-1H-benzimidazole-2-thiol (I). The compound I was further reacted with different derivatives of 2-chloro-N-phenylacetamide (IIa-j) prepared by reacting differently substituted anilines with chloroacetylchloride and triethylamine in DMF (solvent); resulting in formation of fluorobenzimidazoles IIIa-j. The compounds IIIa-j were characterized by spectral analysis viz. 1H NMR, 13C NMR, mass spectra, elemental analysis and IR. All these compounds were screened in vitro for their antimicrobial activity against Gram-positive (S. aureus and E. faecalis) and Gram-negative bacterial (E. coli and P.aeruginosa) strains as well as fungi (A. niger and C. albicans). Some of the compounds exhibited promising results (in MIC) against Gram-negative bacterial strains.

scholarly journals Synthesis and Antimicrobial Evaluations of Sulfur Inserted Fluoro-Benzimidazoles

2021 ◽  
Vol 33 (7) ◽  
pp. 1525-1529
Author(s):  
Parmesh Kumar Dwivedi ◽  
Devdutt Chaturvedi
Keyword(s):  
Antimicrobial Agents ◽  
Bacterial Strains ◽  
Substituted Anilines ◽  
Gram Positive ◽  
Gram Negative ◽  
E Coli ◽  
New Compounds ◽  
Derivatives Of ◽  
Multiple Step

A new series of fluorinated sulfur inserted benzimidazole analogues Za-i were synthesized and characterized. The new compounds were screened for their antimicrobial and antioxidant potential. The synthesized compounds were obtained by multiple step synthesis, initiating from the synthesis of 5-(difluoromethoxy)-1H-benzimidazole-2-thiol X. The compounds Ya-i prepared by reacting differently substituted anilines with chloroacetylchloride and triethylamine in DMF. Finally, the compound X was reacted with different derivatives of 2-chloro-N-phenylacetamide resulting in formation of titled compounds Za-i. The synthesized compounds (Za-Zi) were characterized by spectral analysis viz.1H & 13C NMR, mass spectra, elemental analysis and IR. The in vitro antimicrobial potential against Gram-positive (S. aureus and E. faecalis) and Gram-negative bacterial (E. coli and P.aeruginosa) strains as well as fungi (A. niger and C. albicans) was recorded for the obtained compounds. Some of the compounds exhibited encouraging results (in MIC) against Gram-positive and Gram-negative bacterial strains. These studies thus suggest that the designed sulfur inserted fluoro-benzimidazoles scaffold may serve as new promising template for further amplification as antimicrobial agents.

In Vitro Antibacterial Activities and Mechanisms of Action of Fatty Acid Monoglycerides Against Four Foodborne Bacteria

2020 ◽  
Vol 83 (2) ◽  
pp. 331-337
Author(s):  
WENYUE WANG ◽  
RUI WANG ◽  
GUIJU ZHANG ◽  
FANGLI CHEN ◽  
BAOCAI XU
Keyword(s):  
Antibacterial Activity ◽  
Antibacterial Activities ◽  
Carbon Chain ◽  
Antimicrobial Activities ◽  
Inhibitory Effect ◽  
Gram Positive ◽  
Gram Negative ◽  
E Coli ◽  
Alkaline Conditions

ABSTRACT Naturally occurring monoglyceride esters of fatty acids have been associated with a broad spectrum of antimicrobial activities. We used an automated turbidimetric method to measure the MIC and assess the antimicrobial activity of five monoglycerides (monocaprin, monolaurin, monomyristin, monopalmitin, and monostearin) against pathogenic strains of Staphylococcus aureus, Bacillus subtilis, Pseudomonas aeruginosa, and Escherichia coli. The antibacterial activity of monocaprin was highest because its carbon chain is shorter than those of other monoglycerides. The MICs of monocaprin against S. aureus, B. subtilis, P. aeruginosa, and E. coli were 0.32, 0.32, 2.5, and 2.5 mg/mL, respectively. Monocaprin had antibacterial activity under neutral and alkaline conditions (pH 7.0 to 9.0) but had no inhibitory effect on S. aureus, B. subtilis, and E. coli under weakly acidic conditions (pH 6.0). The antibacterial mechanism of monocaprin against gram-positive strains (S. aureus and B. subtilis) resulted from destruction of the cell membrane. In contrast, the antibacterial activity of monocaprin against gram-negative strains (P. aeruginosa and E. coli) was attributed to damage to lipopolysaccharides in the cell walls. Because of its inhibitory effect on both gram-positive and gram-negative bacteria, monocaprin could be used as an antibacterial additive in the food industry. HIGHLIGHTS

scholarly journals Novel Synthesis and Antimicrobial Activities of Thiazino-Oxazine Derivatives

2018 ◽  
Vol 10 (4) ◽  
Author(s):  
Dr.Pravina B. Piste
Keyword(s):  
Spectral Analysis ◽  
Heterocyclic Compounds ◽  
Antibacterial Activities ◽  
Antimicrobial Activities ◽  
Plate Method ◽  
Standard Drug ◽  
Gram Negative ◽  
E Coli ◽  
Novel Synthesis

In the designing and synthesis of new heterocyclic compounds, containing two different pharmacophores, we have carried out new series of 3-(4-chlorophenyl)-4-methylidene-4,8-dihydro-2H,5H-1,3-thiazino[5,4-e]-1,3-oxazine-2,5,7(3H)-trione derivatives (5a-5k) in good yields from the cyclization of 5-[(1E)-N- (4-chlorophenyl) ethanimidoyl] -4-hydroxy- 2H-1,3- thiazine-2,6(3H)-dione derivatives (4a-4k) with triphosgene. All the synthesized compounds (5a-5k) were confirmed by spectral analysis. The synthesized compounds (5a-5k) were screened in vitro for their antibacterial activities against S. subtilis (gram positive) and E. coli. (gram negative) while antifungal activity against C. albicans by cup plate method. Some of the products of series were found to have quite good activities as compared to the standard drug streptomycin and flucanozole.

Synthesis and Characterization of Novel 1,3,5-Thiadiazine Derivatives Integrated with Quinoline Moiety as Potent Antimicrobial Agents

2020 ◽  
Vol 5 (2) ◽  
pp. 149-155
Author(s):  
M. Idrees ◽  
Naqui J. Siddiqui ◽  
Yogita G. Bodkhe ◽  
Satish Kola
Keyword(s):  
13C Nmr ◽  
Mass Spectra ◽  
Antimicrobial Agents ◽  
Synthesis And Characterization ◽  
Pathogenic Microorganism ◽  
Bacterial Strains ◽  
Gram Negative ◽  
E Coli

An expeditious synthesis of series of novel 1,3,5-thiadiazine (5a-f) and (6a-f) derivatives have been described. These compounds were synthesized by reaction of 1-(N-((6-methyl-2-(p-tolyloxy)quinoline- 3-yl)methylene)carbamimidoyl)-3-arylthiourea (3a-b) derivatives with N-aryl isocyanodichloride (4a-c) in chloroform followed by basification with dilute NH4OH to give the target compounds 5a-f; which were acetylated further to afford six novel 1,3,5-thiadiazin-3-(6H)-yl)ethanone (6a-f) derivatives. Synthesis of intermediate compounds 3a-b was obtained by reacting 6-methyl-2-(p-tolyloxy)quinoline-3- carbaldehyde (2a) and 1-carbamimidoyl-3-aryllthiourea (1a-b) in chloroform. Structures of compounds 5a-f and 6a-f were established by FTIR, 1H & 13C NMR, mass spectra and further supported by elemental analysis. All synthesized compounds were investigated for their in vitro antimicrobial screening against a panel of pathogenic microorganism comprising S. aureus as Gram positive while E. coli, P. vulgaris, S. typhi as Gram-negative bacterial strains.

scholarly journals IN SILICO AND IN VITRO ASSAY OF HGV ANALOGUE AS ANTIBACTERIAL

2019 ◽  
pp. 78-85
Author(s):  
Bambang Wijianto ◽  
RITMALENI . ◽  
HARI PURNOMO ◽  
ARIEF NURROCHMAD
Keyword(s):  
In Silico ◽  
Aldol Condensation ◽  
Antibacterial Activities ◽  
In Vitro Assay ◽  
Dilution Method ◽  
Qsar Study ◽  
Vitro Assay ◽  
E Coli ◽  
Parameterized Model

Objective: The objective of this research was to design a new analogue compound, hexagamavunon (HGV). Methods: New design of analogue compound, HGV, was performed by QSAR study using BuildQSAR program. In this QSAR study, parameterized model (PM3) method using the Polak-Ribière algorithm was applied to calculate the optimal geometric structures of the used compounds. The new analogue compound, HGV had been synthesized using aldol condensation reaction. The assay of antibacterial activities was performed using the dilution method. Molecular operating environment (MOE) program was used for protocol docking. Results: The results of QSAR study reveal the good relationship of antibacterial activities. The in vitro antibacterial activities of 2,6-bis((E)-3,5-dibromo-4-hydroxybenzylidene) cyclohexan-1-one (A113) indicates the good potential to against S. aureus, B. subtilis and E. coli with IC50 27.3 μg/ml, 30.9 μg/ml, 32 μg/ml respectively. This is in accordance with the in silico evaluation showing that 2,6-bis((E)-3,5-dibromo-4-hydroxybenzylidene) cyclohexan-1-one has lower docking score than both amoxicillin and cefoxitin do as the native ligand of receptor 3MZE. Conclusion: Based on in silico and in vitro assay, 2,6-bis((E)-3,5-dibromo-4-hydroxybenzylidene) cyclohexan-1-one (A113) has good antibacterial activities against S. aureus, B. subtilis, and E. coli.

scholarly journals Discovery of the Elusive UDP-Diacylglucosamine Hydrolase in the Lipid A Biosynthetic Pathway in Chlamydia trachomatis

mBio ◽  
2016 ◽  
Vol 7 (2) ◽  
Author(s):  
Hayley E. Young ◽  
Jinshi Zhao ◽  
Jeffrey R. Barker ◽  
Ziqiang Guan ◽  
Raphael H. Valdivia ◽  
...  
Keyword(s):  
Chlamydia Trachomatis ◽  
Biosynthetic Pathway ◽  
Lipid A ◽  
Genomic Library ◽  
Essential Gene ◽  
Gram Negative Bacteria ◽  
Gram Negative ◽  
E Coli ◽  
Pyrophosphatase Activity

ABSTRACT Constitutive biosynthesis of lipid A via the Raetz pathway is essential for the viability and fitness of Gram-negative bacteria, including Chlamydia trachomatis . Although nearly all of the enzymes in the lipid A biosynthetic pathway are highly conserved across Gram-negative bacteria, the cleavage of the pyrophosphate group of UDP-2,3-diacyl-GlcN (UDP-DAGn) to form lipid X is carried out by two unrelated enzymes: LpxH in beta- and gammaproteobacteria and LpxI in alphaproteobacteria. The intracellular pathogen C. trachomatis lacks an ortholog for either of these two enzymes, and yet, it synthesizes lipid A and exhibits conservation of genes encoding other lipid A enzymes. Employing a complementation screen against a C. trachomatis genomic library using a conditional-lethal lpxH mutant Escherichia coli strain, we have identified an open reading frame (Ct461, renamed lpxG ) encoding a previously uncharacterized enzyme that complements the UDP-DAGn hydrolase function in E. coli and catalyzes the conversion of UDP-DAGn to lipid X in vitro . LpxG shows little sequence similarity to either LpxH or LpxI, highlighting LpxG as the founding member of a third class of UDP-DAGn hydrolases. Overexpression of LpxG results in toxic accumulation of lipid X and profoundly reduces the infectivity of C. trachomatis , validating LpxG as the long-sought-after UDP-DAGn pyrophosphatase in this prominent human pathogen. The complementation approach presented here overcomes the lack of suitable genetic tools for C. trachomatis and should be broadly applicable for the functional characterization of other essential C. trachomatis genes . IMPORTANCE Chlamydia trachomatis is a leading cause of infectious blindness and sexually transmitted disease. Due to the lack of robust genetic tools, the functions of many Chlamydia genes remain uncharacterized, including the essential gene encoding the UDP-DAGn pyrophosphatase activity for the biosynthesis of lipid A, the membrane anchor of lipooligosaccharide and the predominant lipid species of the outer leaflet of the bacterial outer membrane. We designed a complementation screen against the C. trachomatis genomic library using a conditional-lethal mutant of E. coli and identified the missing essential gene in the lipid A biosynthetic pathway, which we designated lpxG . We show that LpxG is a member of the calcineurin-like phosphatases and displays robust UDP-DAGn pyrophosphatase activity in vitro . Overexpression of LpxG in C. trachomatis leads to the accumulation of the predicted lipid intermediate and reduces bacterial infectivity, validating the in vivo function of LpxG and highlighting the importance of regulated lipid A biosynthesis in C. trachomatis .

Antibiotic potential of some synthesized derivatives of C-9154 antibiotic

2020 ◽  
Vol 15 (2) ◽  
pp. 52-58
Author(s):  
Isaac Asusheyi Bello ◽  
Isaac Asusheyi Bello ◽  
George Iloegbulam Ndukwe ◽  
Joseph Olorunju Amupitan ◽  
Rachael Gbekele Ayo ◽  
...  
Keyword(s):  
Structural Modification ◽  
Functional Group ◽  
Gram Negative Bacteria ◽  
Gram Negative ◽  
E Coli ◽  
Gram Positive Bacteria ◽  
Derivatives Of ◽  
Acid Functional Group ◽  
Better Than

Structural modification of the C-9154 antibiotic in an attempt to simultaneously improve its activity and lower its toxicity led to the synthesis of an analogue of the C-9154 antibiotic and six derivatives of this analogue. The significant reduction of the polarity of the synthesized analogue in the derivatives to increase permeability across cell membranes was achieved by conversion of the highly polar carboxylic group to the nonpolar ester functional groups. The compounds were synthesized by condensation of 4-nitroaniline with maleic anhydride and then conversion of the terminal carboxylic acid functional group to an ester functional group using a thionyl chloride-mediated esterification. The in vitro biological activity using gram positive bacteria (MRSA, S. pyogenes, B. subtilis, and C. ulcerans), gram negative bacteria (E. coli, P. mirabilis, P. aeruginosa, S. typhii, S. dysenteriae, and K. pneumonia and some fungi (C. albicans, A. nigre and T. rubrum), showed that the derivatives were more active than their respective analogue and significantly better than the standard antibiotics (Sparfloxacin and Fluconazole) used for comparison, establishing their potential or use as antibiotics. The derivatives exhibited activity at concentrations as low as 0.625μg/mL while the analogue was active at 2.5μg/mL. These values were higher than results obtained for the standard drugs which showed activity at concentrations of 5 μg/mL. The derivatives however did not show activity against A. nigre whereas the analogue was active against it. Keywords: C-9154 Antibiotic, Bioactivity, Fumaramidmycin, antibacterial, antifungal

scholarly journals PREVALENCE AND MOLECULAR CHARACTERIZATION OF blaCTX-M-15-PRODUCING PATHOGENIC GRAM-NEGATIVE BACTERIA FROM VARIOUS CLINICAL SAMPLES

2018 ◽  
Vol 11 (10) ◽  
pp. 386
Author(s):  
Sindhuja S ◽  
Sureshkumar Bt ◽  
Janaki S ◽  
Thenmozhi S
Keyword(s):  
Molecular Characterization ◽  
Pathogenic Bacteria ◽  
Disk Diffusion ◽  
Diffusion Method ◽  
Clinical Samples ◽  
Gram Negative Bacteria ◽  
Gram Negative ◽  
E Coli

Objective: The objective of this study was to describe the prevalence and molecular characterization of blaCTX-M-15-producing pathogenic Gram-negative bacteria from various clinical samples isolated from clinically suspected patients.Methods: In this study, clinical samples of urine, stool, sputum, and pus were collected from 244 patients with nosocomial infections. The phenotypic identification of extended-spectrum β-lactamases (ESBL) was confirmed by double-disk synergy test and combined disk diffusion test. In vitro, the susceptibility pattern of antimicrobial agents against pathogenic isolates was performed by Kirby–Bauer disk diffusion method. The identification of blaCTX-M-15-producing Escherichia coli was assessed by polymerase chain reaction method.Results: The frequency of ESBL-producing pathogenic bacteria from screened was 6 (46.15%). In vitro, susceptibility to pathogenic bacteria showed that the majority of isolates were highly susceptible to amoxicillin-clavulanic acid (97.87%), ofloxacin (93.33%), and Pseudomonas aeruginosa showed 100% sensitive to ceftazidime, cefotaxime, cefixime, cefoperazone, and meropenem (92.30%). The rates of resistance to other antibiotics varied from <26.66%. Among six tested isolates, only one E. coli isolates showed blaCTX-M-15 gene.Conclusion: Due to the increase of E. coli with multiple ESBL genes, continuous surveillance should be needed in clinical field to use of appropriate antibiotics and the control of infections.

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