Glucose Metabolism byEscherichia coliInhibitsVibrio choleraeIntestinal Colonization of Zebrafish

ABSTRACTTheVibrio choleraeO1 serogroup is responsible for pandemic cholera and is divided into the classical and El Tor biotypes. ClassicalV. choleraeproduces acid when using glucose as a carbon source, whereas El TorV. choleraeproduces the neutral product acetoin when using glucose as a carbon source. An earlier study demonstrated thatEscherichia colistrains that metabolize glucose to acidic by-products drastically reduced the survival ofV. choleraestrainsin vitro. In the present study, zebrafish were fed 1% glucose and either inoculated with singleV. choleraeorE. colistrains or coinfected with bothV. choleraeandE. coli. A significant decrease in classical biotype colonization was observed after glucose feeding due to acid production in the zebrafish intestine. El Tor colonization was unaffected by glucose alone. However, the El Tor strain exhibited significantly lower colonization of the zebrafish when either of the acid-producingE. colistrains was coinoculated in the presence of glucose. AnE. colisugar transport mutant had no effect onV. choleraecolonization even in presence of glucose. Glucose andE. coliproduced a prophylactic effect on El Tor colonization in zebrafish whenE. coliwas inoculated beforeV. choleraeinfection. Thus, the probiotic feeding ofE. coliinhibitsV. choleraecolonization in a natural host. This suggests that a similar inhibitory effect could be seen in cholera patients, especially if a glucose-based oral rehydration solution (ORS) is administered in combination with probioticE. coliduring cholera treatment.

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Role of F1C Fimbriae, Flagella, and Secreted Bacterial Components in the Inhibitory Effect of Probiotic Escherichia coli Nissle 1917 on Atypical Enteropathogenic E. coli Infection

Infection and Immunity ◽

10.1128/iai.01431-13 ◽

2014 ◽

Vol 82 (5) ◽

pp. 1801-1812 ◽

Cited By ~ 23

Author(s):

Sylvia Kleta ◽

Marcel Nordhoff ◽

Karsten Tedin ◽

Lothar H. Wieler ◽

Rafal Kolenda ◽

...

Keyword(s):

Escherichia Coli ◽

Molecular Mechanisms ◽

Inhibitory Effect ◽

Host Cells ◽

Single Infection ◽

Content Type ◽

E Coli ◽

Initial Adhesion

ABSTRACTEnteropathogenicEscherichia coli(EPEC) is recognized as an important intestinal pathogen that frequently causes acute and persistent diarrhea in humans and animals. The use of probiotic bacteria to prevent diarrhea is gaining increasing interest. The probioticE. colistrain Nissle 1917 (EcN) is known to be effective in the treatment of several gastrointestinal disorders. While bothin vitroandin vivostudies have described strong inhibitory effects of EcN on enteropathogenic bacteria, including pathogenicE. coli, the underlying molecular mechanisms remain largely unknown. In this study, we examined the inhibitory effect of EcN on infections of porcine intestinal epithelial cells with atypical enteropathogenicE. coli(aEPEC) with respect to single infection steps, including adhesion, microcolony formation, and the attaching and effacing phenotype. We show that EcN drastically reduced the infection efficiencies of aEPEC by inhibiting bacterial adhesion and growth of microcolonies, but not the attaching and effacing of adherent bacteria. The inhibitory effect correlated with EcN adhesion capacities and was predominantly mediated by F1C fimbriae, but also by H1 flagella, which served as bridges between EcN cells. Furthermore, EcN seemed to interfere with the initial adhesion of aEPEC to host cells by secretion of inhibitory components. These components do not appear to be specific to EcN, but we propose that the strong adhesion capacities enable EcN to secrete sufficient local concentrations of the inhibitory factors. The results of this study are consistent with a mode of action whereby EcN inhibits secretion of virulence-associated proteins of EPEC, but not their expression.

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Characterization of Plasmodium Atg3-Atg8 Interaction Inhibitors Identifies Novel Alternative Mechanisms of Action in Toxoplasma gondii

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01489-17 ◽

2017 ◽

Vol 62 (2) ◽

Cited By ~ 1

Author(s):

Joseph M. Varberg ◽

Kaice A. LaFavers ◽

Gustavo Arrizabalaga ◽

William J. Sullivan

Keyword(s):

Toxoplasma Gondii ◽

Drug Targets ◽

Inhibitory Effect ◽

Protozoan Parasites ◽

Conjugation System ◽

Content Type ◽

Similar Inhibitory Effect ◽

High Concentrations

ABSTRACT Protozoan parasites, including the apicomplexan pathogens Plasmodium falciparum (which causes malaria) and Toxoplasma gondii (which causes toxoplasmosis), infect millions of people worldwide and represent major human disease burdens. Despite their prevalence, therapeutic strategies to treat infections caused by these parasites remain limited and are threatened by the emergence of drug resistance, highlighting the need for the identification of novel drug targets. Recently, homologues of the core autophagy proteins, including Atg8 and Atg3, were identified in many protozoan parasites. Importantly, components of the Atg8 conjugation system that facilitate the lipidation of Atg8 are required for both canonical and parasite-specific functions and are essential for parasite viability. Structural characterization of the P. falciparum Atg3-Atg8 (PfAtg3-Atg8) interaction has led to the identification of compounds that block this interaction. Additionally, many of these compounds inhibit P. falciparum growth in vitro, demonstrating the viability of this pathway as a drug target. Given the essential role of the Atg8 lipidation pathway in Toxoplasma, we sought to determine whether three PfAtg3-Atg8 interaction inhibitors identified in the Medicines for Malaria Venture Malaria Box exerted a similar inhibitory effect in Toxoplasma. While all three inhibitors blocked Toxoplasma replication in vitro at submicromolar concentrations, they did not inhibit T. gondii Atg8 (TgAtg8) lipidation. Rather, high concentrations of two of these compounds induced TgAtg8 lipidation and fragmentation of the parasite mitochondrion, similar to the effects seen following starvation and monensin-induced autophagy. Additionally, we report that one of the PfAtg3-Atg8 interaction inhibitors induces Toxoplasma egress and provide evidence that this is mediated by an increase in intracellular calcium in response to drug treatment.

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Bacterial Microcompartment-Mediated Ethanolamine Metabolism inEscherichia coliUrinary Tract Infection

Infection and Immunity ◽

10.1128/iai.00211-19 ◽

2019 ◽

Vol 87 (8) ◽

Cited By ~ 2

Author(s):

Katherine Dadswell ◽

Sinead Creagh ◽

Edward McCullagh ◽

Mingzhi Liang ◽

Ian R. Brown ◽

...

Keyword(s):

Urinary Tract ◽

Carbon Source ◽

High Performance ◽

Urine Samples ◽

Breakdown Product ◽

Content Type ◽

E Coli ◽

Tract Infections

ABSTRACTUrinary tract infections (UTIs) are common and in general are caused by intestinal uropathogenicEscherichia coli(UPEC) ascending via the urethra. Microcompartment-mediated catabolism of ethanolamine, a host cell breakdown product, fuels the competitive overgrowth of intestinalE. coli, both pathogenic enterohemorrhagicE. coliand commensal strains. During a UTI, urease-negativeE. colibacteria thrive, despite the comparative nutrient limitation in urine. The role of ethanolamine as a potential nutrient source during UTIs is understudied. We evaluated the role of the metabolism of ethanolamine as a potential nitrogen and carbon source for UPEC in the urinary tract. We analyzed infected urine samples by culture, high-performance liquid chromatography, reverse transcription-quantitative PCR, and genomic sequencing. The ethanolamine concentration in urine was comparable to the concentration of the most abundant reported urinary amino acid,d-serine. Transcription of theeutoperon was detected in the majority of urine samples containingE. coliscreened. All sequenced UPEC strains had conservedeutoperons, while metabolic genotypes previously associated with UTI (dsdCXA,metE) were mainly limited to phylogroup B2.In vitroethanolamine was found to be utilized as a sole source of nitrogen by UPEC strains. The metabolism of ethanolamine in artificial urine medium (AUM) induced metabolosome formation and provided a growth advantage at the physiological levels found in urine. Interestingly,eutE(which encodes acetaldehyde dehydrogenase) was required for UPEC strains to utilize ethanolamine to gain a growth advantage in AUM, suggesting that ethanolamine is also utilized as a carbon source. These data suggest that urinary ethanolamine is a significant additional carbon and nitrogen source for infectingE. colistrains.

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Flavone-Rich Fractions and Extracts from Oroxylum indicum and Their Antibacterial Activities against Clinically Isolated Zoonotic Bacteria and Free Radical Scavenging Effects

Molecules ◽

10.3390/molecules26061773 ◽

2021 ◽

Vol 26 (6) ◽

pp. 1773

Author(s):

Patchima Sithisarn ◽

Piyanuch Rojsanga ◽

Pongtip Sithisarn

Keyword(s):

Antibacterial Activities ◽

Inhibitory Effect ◽

Total Flavonoid ◽

Total Phenolic ◽

Antibacterial Effects ◽

E Coli ◽

Young Fruit ◽

Oroxylum Indicum ◽

Zoonotic Bacteria

Oroxylum indicum extracts from the seeds collected from Lampang and Pattani provinces in Thailand, and young fruits and flowers exhibited in vitro display antioxidant and antibacterial activities against clinically isolated zoonotic bacteria including Staphylococcus intermedius, Streptococcus suis, Pseudomonas aeruginosa, β-hemolytic Escherichia coli and Staphylococcus aureus. The orange crystals and yellow precipitates were obtained from the preparation processes of the seed extracts. The orange-red crystals from the seeds collected from Lampang province exhibited strong in vitro 2,2-diphenyl-1-picrylhydrazyl (DPPH) scavenging effects (EC50 value = 25.99 ± 3.30 μg/mL) and antibacterial effects on S. intermedius and β-hemolytic E. coli while the yellow precipitate from the same source exhibited only antioxidant activity. Quantitative analysis of phytochemicals in O. indicum samples by spectrophotometric and HPLC techniques showed that they contained different amounts of total phenolic, total flavonoid and three major flavones; baicalin, baicalein and chrysin contents. Young fruit extract, which contained low amounts of flavone contents, still promoted antibacterial effects against the tested bacteria with IC50 values lower than 1 mg/mL and MIC values between 4 to 10 mg/mL in S. intermedius, S. aureus and S suis while higher IC50 and MIC values against P. aeruginosa and β-hemolytic E. coli were found. From scanning electron microscopy, the extract of the young fruit of O. indicum promoted morphological changes in the bacterial cells by disrupting the bacterial cell walls, inducing leakage of the cellular content, and generating the abnormal accumulation of cells. The mechanism of action of the extract for this antibacterial effect may be the disruption of the cell membrane and abnormal cell aggregations. Regression analysis of the results suggests the correlation between total phenolic and total flavonoid contents and antioxidant and antibacterial effects. Baicalin was found to have a high correlation with an inhibitory effect against β-hemolytic E. coli while three unidentified peaks, which could be flavones, showed high correlations with an inhibitory effect against S. intermedius, S. suis, P. aeruginosa and S. aureus.

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Enhancing Terpene Yield from Sugars via Novel Routes to 1-Deoxy-d-Xylulose 5-Phosphate

Applied and Environmental Microbiology ◽

10.1128/aem.02920-14 ◽

2014 ◽

Vol 81 (1) ◽

pp. 130-138 ◽

Cited By ~ 30

Author(s):

James Kirby ◽

Minobu Nishimoto ◽

Ruthie W. N. Chow ◽

Edward E. K. Baidoo ◽

George Wang ◽

...

Keyword(s):

Bacterial Species ◽

Xylose Reductase ◽

Pentose Phosphate ◽

Terpene Biosynthesis ◽

Content Type ◽

E Coli ◽

Pathway Expression ◽

Terpene Synthesis ◽

Selection For

ABSTRACTTerpene synthesis in the majority of bacterial species, together with plant plastids, takes place via the 1-deoxy-d-xylulose 5-phosphate (DXP) pathway. The first step of this pathway involves the condensation of pyruvate and glyceraldehyde 3-phosphate by DXP synthase (Dxs), with one-sixth of the carbon lost as CO2. A hypothetical novel route from a pentose phosphate to DXP (nDXP) could enable a more direct pathway from C5sugars to terpenes and also circumvent regulatory mechanisms that control Dxs, but there is no enzyme known that can convert a sugar into its 1-deoxy equivalent. Employing a selection for complementation of adxsdeletion inEscherichia coligrown on xylose as the sole carbon source, we uncovered two candidate nDXP genes. Complementation was achieved either via overexpression of the wild-typeE. coliyajOgene, annotated as a putative xylose reductase, or via various mutations in the nativeribBgene.In vitroanalysis performed with purified YajO and mutant RibB proteins revealed that DXP was synthesized in both cases from ribulose 5-phosphate (Ru5P). We demonstrate the utility of these genes for microbial terpene biosynthesis by engineering the DXP pathway inE. colifor production of the sesquiterpene bisabolene, a candidate biodiesel. To further improve flux into the pathway from Ru5P, nDXP enzymes were expressed as fusions to DXP reductase (Dxr), the second enzyme in the DXP pathway. Expression of a Dxr-RibB(G108S) fusion improved bisabolene titers more than 4-fold and alleviated accumulation of intracellular DXP.

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A Rhodobacter sphaeroides Protein Mechanistically Similar to Escherichia coli DksA Regulates Photosynthetic Growth

mBio ◽

10.1128/mbio.01105-14 ◽

2014 ◽

Vol 5 (3) ◽

Cited By ~ 7

Author(s):

Christopher W. Lennon ◽

Kimberly C. Lemmer ◽

Jessica L. Irons ◽

Max I. Sellman ◽

Timothy J. Donohue ◽

...

Keyword(s):

Escherichia Coli ◽

Structure Function ◽

Rhodobacter Sphaeroides ◽

Fatty Acid Content ◽

Regulatory Protein ◽

Growth Conditions ◽

Globular Domain ◽

Content Type ◽

E Coli

ABSTRACTDksA is a global regulatory protein that, together with the alarmone ppGpp, is required for the “stringent response” to nutrient starvation in the gammaproteobacteriumEscherichia coliand for more moderate shifts between growth conditions. DksA modulates the expression of hundreds of genes, directly or indirectly. Mutants lacking a DksA homolog exhibit pleiotropic phenotypes in other gammaproteobacteria as well. Here we analyzed the DksA homolog RSP2654 in the more distantly relatedRhodobacter sphaeroides, an alphaproteobacterium. RSP2654 is 42% identical and similar in length toE. coliDksA but lacks the Zn finger motif of theE. coliDksA globular domain. Deletion of the RSP2654 gene results in defects in photosynthetic growth, impaired utilization of amino acids, and an increase in fatty acid content. RSP2654 complements the growth and regulatory defects of anE. colistrain lacking thedksAgene and modulates transcriptionin vitrowithE. coliRNA polymerase (RNAP) similarly toE. coliDksA. RSP2654 reduces RNAP-promoter complex stabilityin vitrowith RNAPs fromE. coliorR. sphaeroides, alone and synergistically with ppGpp, suggesting that even though it has limited sequence identity toE. coliDksA (DksAEc), it functions in a mechanistically similar manner. We therefore designate the RSP2654 protein DksARsp. Our work suggests that DksARsphas distinct and important physiological roles in alphaproteobacteria and will be useful for understanding structure-function relationships in DksA and the mechanism of synergy between DksA and ppGpp.IMPORTANCEThe role of DksA has been analyzed primarily in the gammaproteobacteria, in which it is best understood for its role in control of the synthesis of the translation apparatus and amino acid biosynthesis. Our work suggests that DksA plays distinct and important physiological roles in alphaproteobacteria, including the control of photosynthesis inRhodobacter sphaeroides. The study of DksARsp, should be useful for understanding structure-function relationships in the protein, including those that play a role in the little-understood synergy between DksA and ppGpp.

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Cerebrovascular characterization of clazosentan, the first nonpeptide endothelin receptor antagonist clinically effective for the treatment of cerebral vasospasm. Part I: Inhibitory effect on endothelinA receptor—mediated contraction

Journal of Neurosurgery ◽

10.3171/jns.2005.102.6.1101 ◽

2005 ◽

Vol 102 (6) ◽

pp. 1101-1107 ◽

Cited By ~ 23

Author(s):

Hartmut Vatter ◽

Michael Zimmermann ◽

Veronika Tesanovic ◽

Andreas Raabe ◽

Lothar Schilling ◽

...

Keyword(s):

Receptor Antagonist ◽

Cerebral Vasospasm ◽

Isometric Force ◽

Inhibitory Effect ◽

Affinity Constant ◽

Dependent Manner ◽

Content Type ◽

The Right ◽

Fine Print

Object. The central role of endothelin (ET)—1 in the development of cerebral vasospasm after subarachnoid hemorrhage is indicated by the successful treatment of this vasospasm in several animal models by using selective ETA receptor antagonists. Clazosentan is a selective ETA receptor antagonist that provides for the first time clinical proof that ET-1 is involved in the pathogenesis of cerebral vasospasm. The aim of the present investigation was, therefore, to define the pharmacological properties of clazosentan that affect ETA receptor—mediated contraction in the cerebrovasculature. Methods. Isometric force measurements were performed in rat basilar artery (BA) ring segments with (E+) and without (E−) endothelial function. Concentration effect curves (CECs) were constructed by cumulative application of ET-1 or big ET-1 in the absence or presence of clazosentan (10−9, 10−8, and 10−7 M). The inhibitory potency of clazosentan was determined by the value of the affinity constant (pA2). The CECs for contraction induced by ET-1 and big ET-1 were shifted to the right in the presence of clazosentan in a parallel dose-dependent manner, which indicates competitive antagonism. The pA2 values for ET-1 were 7.8 (E+) and 8.6 (E−) and the corresponding values for big ET-1 were 8.6 (E+) and 8.3 (E−). Conclusions. The present data characterize clazosentan as a potent competitive antagonist of ETA receptor—mediated constriction of the cerebrovasculature by ET-1 and its precursor big ET-1. These functional data may also be used to define an in vitro profile of an ET receptor antagonist with a high probability of clinical efficacy.

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Activity of Ceftazidime-Avibactam against Fluoroquinolone-Resistant Enterobacteriaceae and Pseudomonas aeruginosa

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.05136-14 ◽

2015 ◽

Vol 59 (6) ◽

pp. 3059-3065 ◽

Cited By ~ 14

Author(s):

C. Pitart ◽

F. Marco ◽

T. A. Keating ◽

W. W. Nichols ◽

J. Vila

Keyword(s):

Pseudomonas Aeruginosa ◽

Resistant Mutant ◽

Fluoroquinolone Resistance ◽

Cross Resistance ◽

Content Type ◽

E Coli ◽

Microdilution Method ◽

Broth Microdilution Method ◽

The Impact

ABSTRACTCeftazidime-avibactam and comparator antibiotics were tested by the broth microdilution method against 200Enterobacteriaceaeand 25Pseudomonas aeruginosastrains resistant to fluoroquinolones (including strains with the extended-spectrum β-lactamase [ESBL] phenotype and ceftazidime-resistant strains) collected from our institution. The MICs and mechanisms of resistance to fluoroquinolone were also studied. Ninety-nine percent of fluoroquinolone-resistantEnterobacteriaceaestrains were inhibited at a ceftazidime-avibactam MIC of ≤4 mg/liter (using the susceptible CLSI breakpoint for ceftazidime alone as a reference). Ceftazidime-avibactam was very active against ESBLEscherichia coli(MIC90of 0.25 mg/liter), ESBLKlebsiella pneumoniae(MIC90of 0.5 mg/liter), ceftazidime-resistant AmpC-producing species (MIC90of 1 mg/liter), non-ESBLE. coli(MIC90of ≤0.125 mg/liter), non-ESBLK. pneumoniae(MIC90of 0.25 mg/liter), and ceftazidime-nonresistant AmpC-producing species (MIC90of ≤0.5 mg/liter). Ninety-six percent of fluoroquinolone-resistantP. aeruginosastrains were inhibited at a ceftazidime-avibactam MIC of ≤8 mg/liter (using the susceptible CLSI breakpoint for ceftazidime alone as a reference), with a MIC90of 8 mg/liter. Additionally, fluoroquinolone-resistant mutants from each species tested were obtainedin vitrofrom two strains, one susceptible to ceftazidime and the other a β-lactamase producer with a high MIC against ceftazidime but susceptible to ceftazidime-avibactam. Thereby, the impact of fluoroquinolone resistance on the activity of ceftazidime-avibactam could be assessed. The MIC90values of ceftazidime-avibactam for the fluoroquinolone-resistant mutant strains ofEnterobacteriaceaeandP. aeruginosawere ≤4 mg/liter and ≤8 mg/liter, respectively. We conclude that the presence of fluoroquinolone resistance does not affectEnterobacteriaceaeandP. aeruginosasusceptibility to ceftazidime-avibactam; that is, there is no cross-resistance.

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Agreement Assessment of Tigecycline Susceptibilities Determined by the Disk Diffusion and Broth Microdilution Methods among Commonly Encountered Resistant Bacterial Isolates: Results from the TigecyclineIn VitroSurveillance in Taiwan (TIST) Study, 2008 to 2010

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.05879-11 ◽

2011 ◽

Vol 56 (3) ◽

pp. 1414-1417 ◽

Cited By ~ 21

Author(s):

Jien-Wei Liu ◽

Wen-Chien Ko ◽

Cheng-Hua Huang ◽

Chun-Hsing Liao ◽

Chin-Te Lu ◽

...

Keyword(s):

Susceptibility Testing ◽

Total Error ◽

Error Rates ◽

Resistant Bacteria ◽

Drug Resistant ◽

Broth Microdilution ◽

Content Type ◽

E Coli ◽

Drug Resistant Bacteria

ABSTRACTThe TigecyclineIn VitroSurveillance in Taiwan (TIST) study, initiated in 2006, is a nationwide surveillance program designed to longitudinally monitor thein vitroactivity of tigecycline against commonly encountered drug-resistant bacteria. This study compared thein vitroactivity of tigecycline against 3,014 isolates of clinically important drug-resistant bacteria using the standard broth microdilution and disk diffusion methods. Species studied included methicillin-resistantStaphylococcus aureus(MRSA;n= 759), vancomycin-resistantEnterococcus faecium(VRE;n= 191), extended-spectrum β-lactamase (ESBL)-producingEscherichia coli(n= 602), ESBL-producingKlebsiella pneumoniae(n= 736), andAcinetobacter baumannii(n= 726) that had been collected from patients treated between 2008 and 2010 at 20 hospitals in Taiwan. MICs and inhibition zone diameters were interpreted according to the currently recommended U.S. Food and Drug Administration (FDA) criteria and the European Committee on Antimicrobial Susceptibility Testing (EUCAST) criteria. The MIC90values of tigecycline against MRSA, VRE, ESBL-producingE. coli, ESBL-producingK. pneumoniae, andA. baumanniiwere 0.5, 0.125, 0.5, 2, and 8 μg/ml, respectively. The total error rates between the two methods using the FDA criteria were high: 38.4% for ESBL-producingK. pneumoniaeand 33.8% forA. baumannii. Using the EUCAST criteria, the total error rate was also high (54.6%) forA. baumanniiisolates. The total error rates between these two methods were <5% for MRSA, VRE, and ESBL-producingE. coli. For routine susceptibility testing of ESBL-producingK. pneumoniaeandA. baumanniiagainst tigecycline, the broth microdilution method should be used because of the poor correlation of results between these two methods.

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Synthesis of Some Polysubstituted Nicotinonitriles and Derived Pyrido[2,3-d]pyrimidines asIn VitroCytotoxic and Antimicrobial Candidates

Journal of Chemistry ◽

10.1155/2016/2135893 ◽

2016 ◽

Vol 2016 ◽

pp. 1-12 ◽

Cited By ~ 5

Author(s):

Hassan M. Faidallah ◽

Sherif A. F. Rostom ◽

Khalid A. Khan

Keyword(s):

Cell Line ◽

Colon Carcinoma ◽

Human Tumor ◽

Human Colon ◽

Pyrimidine Ring ◽

Inhibitory Effect ◽

Breast Adenocarcinoma ◽

Human Tumor Cell Lines ◽

E Coli

The synthesis of polysubstituted pyridines, in addition to some derived pyrido[2,3-d]pyrimidine ring systems supported with chemotherapeutically active functionalities, is described. They were evaluated for theirin vitrocytotoxic effects against three different human tumor cell lines (human colon carcinoma HT29, hepatocellular carcinoma Hep-G2, and Caucasian breast adenocarcinoma MCF7). Nine compounds displayed variable cytotoxic potential, among which alkylthio analogs33,34, and37emerged as the most active members, being almost twice as active as doxorubicin against the colon carcinoma HT29 cell line. In addition, the same three analogs showed a clear differential cytotoxic profile as they exhibited a marginal inhibitory effect on the growth of the normal nontransformed human foreskin fibroblast Hs27 cell line. Meanwhile, nineteen compounds were able to exhibit significant antibacterial activity against both Gram-positive and Gram-negative bacteria, together with moderate antifungal activities. The pyrido[2,3-d]pyrimidine-2(1H)-thione30together with its alkylthio derivatives33and34stemmed as the most active antimicrobial members being equipotent to ampicillin againstS. aureus,E. coli,andP. aeruginosa,together with a noticeable antifungal activity againstC. albicans.Compounds33and34could be considered as a promising template for possible dual antimicrobial-anticancer candidates.

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