scholarly journals Characterisation of the antimicrobial mode of action of gallium maltolate

2020 ◽  
Vol 2 (7A) ◽  
Author(s):  
Magdalena Piatek ◽  
Darren Griffith ◽  
Kevin Kavanagh
Keyword(s):  
Mode Of Action ◽  
Galleria Mellonella ◽  
Iron Acquisition ◽  
Structural Similarity ◽  
Opportunistic Pathogen ◽  
Inhibitory Effect ◽  
Label Free ◽  
Iron Storage

To human health worldwide. Existing treatments are becoming inefficacious and therefore there is an urgent need for the development of treatments with alternative modes of action. The use of gallium as an antimicrobial agent has been of interest due to its unconventional mode of action involving the inhibition of iron acquisition and metabolism. The structural similarity and inability to reduce from a trivalent to divalent form under normal physiological conditions allows gallium to act as an iron mimetic and inhibit many iron-dependent biological pathways, respectively. The antimicrobial potential of gallium maltolate (GaM), Ga(III) coordination complex of maltol, was investigated on the opportunistic pathogen Pseudomonas aeruginosa. In vitro and in vivo analyses using Galleria mellonella (greater wax moth) larvae demonstrated the potent bacteriostatic and non-toxic effect of the complex. Subsequent analysis of GaM treated P. aeruginosa via label-free quantitative proteomics provided an insight into the intrinsic mechanisms of action of GaM. Increased expression of iron-storage protein Bacterioferritin B, the HemO component of iron-sulfur clusters and several stress response proteins (Chaperone Proteins ClpB, HtpG and DnaJ) indicate cell stress in response to inhibited iron uptake. Decreased expression of LasA Protease and LasB Elastase quorum-sensing proteins and flagellar motility proteins FlgM and FlgG further demonstrate the growth inhibitory effect of GaM. These findings provide a basis for a better understanding of the mode of action of GaM, a requirement for the improvement of synthesis and efficacy of the treatment.

scholarly journals ace, Which Encodes an Adhesin in Enterococcus faecalis, Is Regulated by Ers and Is Involved in Virulence

2009 ◽  
Vol 77 (7) ◽  
pp. 2832-2839 ◽  
Author(s):  
Francois Lebreton ◽  
Eliette Riboulet-Bisson ◽  
Pascale Serror ◽  
Maurizio Sanguinetti ◽  
Brunella Posteraro ◽  
...  
Keyword(s):  
Enterococcus Faecalis ◽  
Galleria Mellonella ◽  
Animal Experiments ◽  
Opportunistic Pathogen ◽  
Transcriptional Analysis ◽  
Binding Assays ◽  
Mobility Shift ◽  
Reverse Transcription Quantitative Pcr

ABSTRACT Enterococcus faecalis is an opportunistic pathogen that causes numerous infectious diseases in humans and is a major agent of nosocomial infections. In this work, we showed that the recently identified transcriptional regulator Ers (PrfA like), known to be involved in the cellular metabolism and the virulence of E. faecalis, acts as a repressor of ace, which encodes a collagen-binding protein. We characterized the promoter region of ace, and transcriptional analysis by reverse transcription-quantitative PCR and mobility shift protein-DNA binding assays revealed that Ers directly regulates the expression of ace. Transcription of ace appeared to be induced by the presence of bile salts, probably via the deregulation of ers. Moreover, with an ace deletion mutant and the complemented strain and by using an insect (Galleria mellonella) virulence model, as well as in vivo-in vitro murine macrophage models, we demonstrated for the first time that Ace can be considered a virulence factor for E. faecalis. Furthermore, animal experiments revealed that Ace is also involved in urinary tract infection by E. faecalis.

Possible Mode of Action of Ticlopidine: A Novel Inhibitor of Platelet Aggregation

1979 ◽  
Author(s):  
H. Johnson ◽  
J. B. Heywood
Keyword(s):  
Platelet Aggregation ◽  
Mode Of Action ◽  
Potent Inhibitor ◽  
Platelet Reactivity ◽  
Inhibitory Effect ◽  
Thromboxane Synthetase ◽  
Sustained Effect ◽  
Dependent Inhibition

Ticlopidine (T) is weakly active in vitro, but is a potent inhibitor of platelet aggregation induced by ADP, collagen, thrombin, adrenaline, arachidonic acid, prostaglandin (PG) endoperoxide and thromboxane A2 with a sustained effect, when administered to a variety of animal species, including man. Platelets from treated animals were normal in ultrastructure and 14C-ADP binding was not modified by T. Basal PG synthesis was unaffected, whereas aspirin (A) had a marked inhibitory effect. Platelet cyclo-oxygenase and thromboxane synthetase activities were 90.6±12.9 and 96.1±5.3% of control following T treatment. In contrast to A, T had no effect on vascularprostacyclin (PGI2) synthesis, this being 1.4±0.1, 0.5±0.1 and 1.3±0. 3ng/mg wet weight aorta in T and A-treated and control animals respectively. Platelets from T-treated rats were significantly more responsive to inhibition by exogenous PGI2 (0.2-4 ng/ml) and PGE1 (4- 20 ng/ml). when compared with controls. T administration (30-300 mg/kg) resulted in a dose-dependent inhibition of ADP-induced platelet aggregation (26.0- 87. 5%) and enhancement of platelet reactivity to PGI2 (37.0-159.8%). There was a good correlation between these parameters (r=+0.994). T is a potent inhibitor of platelet aggregati on with a novel mode of action. It is not aspirin-like, but may act to potentiate endogenous PGI2 in vivo, possibly through an effect on platelet adenylate cyclase.

scholarly journals THE ACTION OF SULFONAMIDES ON THE RESPIRATION OF BACTERIA AND YEAST

1942 ◽  
Vol 25 (6) ◽  
pp. 805-817 ◽  
Author(s):  
M. G. Sevag ◽  
M. Shelburne ◽  
Stuart Mudd
Keyword(s):  
Structural Similarity ◽  
Inhibitory Effect ◽  
Brewer’S Yeast ◽  
Respiratory Enzymes ◽  
Staph Aureus ◽  
E Coli ◽  
Brewer's Yeast ◽  
Inhibiting Effect

The inhibiting effects of sulfonamide drugs and their derivatives on the anaerobic decarboxylation of pyruvic acid by Staphylococcus aureus, Escherichia coli, baker's and brewer's yeast, and a carboxylase preparation from brewer's yeast have been investigated. These drugs are: sulfanilamide, sulfapyridine, sulfadiazine, sulfamethyldiazine, sulfathiazole, sulfamethylthiazole, sulfanilamido-5-ethyl-4-thiazolone, 2-aminopyrimidine, 2-aminothiazole, and 2-aminopyridine. The sulfathiazole ring appears to exercise decidedly greater specific inhibiting effect on the carboxylases of Staph. aureus and E. coli. The inhibiting effect on yeast carboxylase is non-differentiable among all the substances tried, except sulfamethyldiazine which is completely ineffective on the carboxylases of the organisms studied. The specific inhibitory effect of sulfathiazole on the carboxylases of Staph. aureus and E. coli in comparison to sulfanilamide, sulfapyridine, and sulfadiazine is in harmony with in vivo and in vitro experimental results of other investigators. The results of the present investigation appear to support the hypothesis (1) that sulfonamides exert their bacteriostatic action through chemical affinity for the carrier proteins of certain respiratory enzymes of the bacterial cell, and that this affinity may in part be related to structural similarity between components of the drugs and the corresponding respiratory coenzymes.

MODE OF ACTION OF CLOMIPHENE

1969 ◽  
Vol 60 (4) ◽  
pp. 635-644 ◽  
Author(s):  
J. Hammerstein
Keyword(s):  
Mode Of Action ◽  
Specific Activity ◽  
Direct Action ◽  
Clomiphene Citrate ◽  
Inhibitory Effect ◽  
Isotopic Dilution ◽  
Corpora Lutea ◽  
Isolation And Purification

ABSTRACT The in vitro influence of clomiphene citrate on the incorporation of acetate-1-14C into progesterone by slices of human corpora lutea was studied in 10 experiments using the reverse isotopic dilution technique for the isolation and purification of radioactive progesterone, followed in most instances by crystallization to constant specific activity. As a clear-cut and reproducible result, the formation of progesterone from labelled acetate was considerably diminished in the presence of clomiphene citrate independent of whether the tissues originated from the menstrual cycle or from normal as well as ectopic pregnancies. This inhibitory effect on the biosynthesis of progesterone was intensified by increasing the concentration of clomiphene in the medium. It was demonstrable after 13.3 minutes of incubation as well as after 6 hours. No obvious interference of clomiphene with the stimulating action of HCG on steroidogenesis was found. These findings point to a direct action of clomiphene on the ovary which might also have some bearing on the mode of action of clomiphene in vivo.

scholarly journals A Ferritin Mutant of Mycobacterium tuberculosis Is Highly Susceptible to Killing by Antibiotics and Is Unable To Establish a Chronic Infection in Mice

2012 ◽  
Vol 80 (10) ◽  
pp. 3650-3659 ◽  
Author(s):  
Ruchi Pandey ◽  
G. Marcela Rodriguez
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Iron Homeostasis ◽  
Storage Proteins ◽  
Iron Acquisition ◽  
Intracellular Iron ◽  
Iron Storage ◽  
Content Type ◽  
Iron Storage Proteins

ABSTRACTIron is an essential, elusive, and potentially toxic nutrient for most pathogens, includingMycobacterium tuberculosis. Due to the poor solubility of ferric iron under aerobic conditions, free iron is not found in the host.M. tuberculosisrequires specialized iron acquisition systems to replicate and cause disease. It also depends on a strict control of iron metabolism and intracellular iron levels to prevent iron-mediated toxicity. Under conditions of iron sufficiency,M. tuberculosisrepresses iron acquisition and induces iron storage, suggesting an important role for iron storage proteins in iron homeostasis.M. tuberculosissynthesizes two iron storage proteins, a ferritin (BfrB) and a bacterioferritin (BfrA). The individual contributions of these proteins to the adaptive response ofM. tuberculosisto changes in iron availability are not clear. By generating individual knockout strains ofbfrAandbfrB, the contribution of each one of these proteins to the maintenance of iron homeostasis was determined. The effect of altered iron homeostasis, resulting from impaired iron storage, on the resistance ofM. tuberculosistoin vitroandin vivostresses was examined. The results show that ferritin is required to maintain iron homeostasis, whereas bacterioferritin seems to be dispensable for this function.M. tuberculosislacking ferritin suffers from iron-mediated toxicity, is unable to persist in mice, and, most importantly, is highly susceptible to killing by antibiotics, showing that endogenous oxidative stress can enhance the antibiotic killing of this important pathogen. These results are relevant for the design of new therapeutic strategies againstM. tuberculosis.

scholarly journals Effects of Iron Chelators on the Formation and Development of Aspergillus fumigatus Biofilm

2015 ◽  
Vol 59 (10) ◽  
pp. 6514-6520 ◽  
Author(s):  
Hasan Nazik ◽  
John C. Penner ◽  
Jose A. Ferreira ◽  
Janus A. J. Haagensen ◽  
Kevin Cohen ◽  
...  
Keyword(s):  
Aspergillus Fumigatus ◽  
Biofilm Formation ◽  
Iron Acquisition ◽  
Inhibitory Effect ◽  
Metabolic Effects ◽  
Content Type ◽  
Reference Isolate ◽  
Broth Macrodilution

ABSTRACTIron acquisition is crucial for the growth ofAspergillus fumigatus.A. fumigatusbiofilm formation occursin vitroandin vivoand is associated with physiological changes. In this study, we assessed the effects of Fe chelators on biofilm formation and development. Deferiprone (DFP), deferasirox (DFS), and deferoxamine (DFM) were tested for MIC against a reference isolate via a broth macrodilution method. The metabolic effects (assessed by XTT [2,3-bis[2-methoxy-4-nitro-5-sulfophenyl]-2H-tetrazolium-5-carboxanilide inner salt]) on biofilm formation by conidia were studied upon exposure to DFP, DFM, DFP plus FeCl3, or FeCl3alone. A preformed biofilm was exposed to DFP with or without FeCl3. The DFP and DFS MIC50against planktonicA. fumigatuswas 1,250 μM, and XTT gave the same result. DFM showed no planktonic inhibition at concentrations of ≤2,500 μM. By XTT testing, DFM concentrations of <1,250 μM had no effect, whereas 2,500 μM increased biofilms forming inA. fumigatusor preformed biofilms (P< 0.01). DFP at 156 to 2,500 μM inhibited biofilm formation (P< 0.01 to 0.001) in a dose-responsive manner. Biofilm formation with 625 μM DFP plus any concentration of FeCl3was lower than that in the controls (P< 0.05 to 0.001). FeCl3at ≥625 μM reversed the DFP inhibitory effect (P< 0.05 to 0.01), but the reversal was incomplete compared to the controls (P< 0.05 to 0.01). For preformed biofilms, DFP in the range of ≥625 to 1,250 μM was inhibitory compared to the controls (P< 0.01 to 0.001). FeCl3at ≥625 μM overcame inhibition by 625 μM DFP (P< 0.001). FeCl3alone at ≥156 μM stimulated biofilm formation (P< 0.05 to 0.001). PreformedA. fumigatusbiofilm increased with 2,500 μM FeCl3only (P< 0.05). In a strain survey, various susceptibilities of biofilms ofA. fumigatusclinical isolates to DFP were noted. In conclusion, iron stimulates biofilm formation and preformed biofilms. Chelators can inhibit or enhance biofilms. Chelation may be a potential therapy forA. fumigatus, but we show here that chelators must be chosen carefully. Individual isolate susceptibility assessments may be needed.

scholarly journals Health Potential of Clery Strawberries: Enzymatic Inhibition and Anti-Candida Activity Evaluation

Molecules ◽  
2021 ◽  
Vol 26 (6) ◽  
pp. 1731
Author(s):  
Francesco Cairone ◽  
Giovanna Simonetti ◽  
Anastasia Orekhova ◽  
Maria Antonietta Casadei ◽  
Gokhan Zengin ◽  
...  
Keyword(s):  
Galleria Mellonella ◽  
Inhibitory Effect ◽  
Fragaria Ananassa ◽  
Human Gut ◽  
Enzymatic Inhibition ◽  
Polyphenolic Content ◽  
Onset Of Diabetes ◽  
Flow Charts

Strawberries, belonging to cultivar Clery (Fragaria × ananassa Duchesne ex Weston) and to a graft obtained by crossing Clery and Fragaria vesca L., were chosen for a study on their health potential, with regard to the prevention of chronic and degenerative diseases. Selected samples, coming from fresh and defrosted berries, submitted to different homogenization techniques combined with thermal and microwave treatments, had been previously analyzed in their polyphenolic content and antioxidant capacity. In the present work, these homogenates were evaluated in relation to their enzymatic inhibition activity towards acetylcholinesterase and butyrylcholinesterase, α-amylase, α-glucosidase and tyrosinase. All these enzymes, involved in the onset of diabetes, and neurodegenerative and other chronic diseases, were modulated by the tested samples. The inhibitory effect on tyrosinase and cholinesterase was the most valuable. Antifungal activity against Candida albicans, recently shown to play a crucial role in human gut diseases as well as diabetes, rheumatoid arthritis and Alzheimer’s disease, was also shown in vitro and confirmed by the in vivo text on Galleria mellonella. Overall, the obtained results confirm once again the health potential of strawberries; however, the efficacy is dependent on high quality products submitted to correct processing flow charts.

scholarly journals c-di-AMP is essential for the virulence of Enterococcus faecalis

2021 ◽  
Author(s):  
Shivani Kundra ◽  
Ling Ning Lam ◽  
Jessica K. Kajfasz ◽  
Leila Casella ◽  
Marissa J Andersen ◽  
...  
Keyword(s):  
Enterococcus Faecalis ◽  
Biofilm Formation ◽  
Galleria Mellonella ◽  
Ex Vivo ◽  
Biological Significance ◽  
Opportunistic Pathogen ◽  
Bacterial Fitness ◽  
Key Aspects

Second messenger nucleotides are produced by bacteria in response to environmental stimuli and play a major role in the regulation of processes associated with bacterial fitness, including but not limited to osmoregulation, envelope homeostasis, central metabolism, and biofilm formation. In this study, we uncovered the biological significance of c-di-AMP in the opportunistic pathogen Enterococcus faecalis by isolating and characterizing strains lacking genes responsible for c-di-AMP synthesis (cdaA) and degradation (dhhP and gdpP). Using complementary approaches, we demonstrated that either complete loss of c-di-AMP (ΔcdaA strain) or c-di-AMP accumulation (ΔdhhP, ΔgdpP and ΔdhhPΔgdpP strains) drastically impaired general cell fitness and virulence of E. faecalis. In particular, the ΔcdaA strain was highly sensitive to envelope-targeting antibiotics, was unable to multiply and quickly lost viability in human serum or urine ex vivo, and was avirulent in an invertebrate (Galleria mellonella) and in two catheter-associated mouse infection models that recapitulate key aspects of enterococcal infections in humans. In addition to evidence linking these phenotypes to altered activity of metabolite and peptide transporters and inability to maintain osmobalance, we found that the attenuated virulence of ΔcdaA could be also attributed to a defect in Ebp pilus production and activity that severely impaired biofilm formation under both in vitro and in vivo conditions. Collectively, these results reveal that c-di-AMP signaling is essential for E. faecalis pathogenesis and a desirable target for drug development.

scholarly journals c-di-AMP is essential for the virulence of Enterococcus faecalis

2021 ◽  
Author(s):  
Shivani Kundra ◽  
Ling Ning Lam ◽  
Jessica K. Kajfasz ◽  
Leila G. Casella ◽  
Marissa J. Andersen ◽  
...  
Keyword(s):  
Enterococcus Faecalis ◽  
Biofilm Formation ◽  
Galleria Mellonella ◽  
Ex Vivo ◽  
Biological Significance ◽  
Opportunistic Pathogen ◽  
Bacterial Fitness ◽  
Key Aspects

Second messenger nucleotides are produced by bacteria in response to environmental stimuli and play a major role in the regulation of processes associated with bacterial fitness, including but not limited to osmoregulation, envelope homeostasis, central metabolism, and biofilm formation. In this study, we uncovered the biological significance of c-di-AMP in the opportunistic pathogen Enterococcus faecalis by isolating and characterizing strains lacking genes responsible for c-di-AMP synthesis ( cdaA ) and degradation ( dhhP and gdpP ). Using complementary approaches, we demonstrated that either complete loss of c-di-AMP (Δ cdaA strain) or c-di-AMP accumulation (Δ dhhP , Δ gdpP and Δ dhhP Δ gdpP strains) drastically impaired general cell fitness and virulence of E. faecalis . In particular, the Δ cdaA strain was highly sensitive to envelope-targeting antibiotics, was unable to multiply and quickly lost viability in human serum or urine ex vivo , and was virtually avirulent in an invertebrate ( Galleria mellonella ) and in two catheter-associated mouse infection models that recapitulate key aspects of enterococcal infections in humans. In addition to evidence linking these phenotypes to altered activity of metabolite and peptide transporters and inability to maintain osmobalance, we found that the attenuated virulence of Δ cdaA could be also attributed to a defect in Ebp pilus production and activity that severely impaired biofilm formation under both in vitro and in vivo conditions. Collectively, these results demonstrate that c-di-AMP signaling is essential for E. faecalis pathogenesis and a desirable target for drug development.

scholarly journals 787. The Addition of Avibactam Augments the Activity of Piperacillin Against Mycobacterium abscessus in vitro, and Is Effective in Treating M. abscessus Infection in a Galleria mellonella in vivo Model

2018 ◽  
Vol 5 (suppl_1) ◽  
pp. S281-S282
Author(s):  
Michal Meir ◽  
Daniel Barkan
Keyword(s):  
Galleria Mellonella ◽  
Inhibitory Effect ◽  
Mycobacterium Abscessus ◽  
In Vivo Model ◽  
Great Promise ◽  
Infection Model ◽  
In Vivo Models ◽  
Antimicrobial Treatments

Abstract Background Mycobacterium abscessus is an emerging multi-drug-resistant pathogen, harboring the β-lactamse BlaMAB. Avibactam is a non-β-lactam, β-lactamase inhibitor shown to inhibit BlaMAB and improve the efficacy of ampicillin for M. abscessus infections in in vitro and in vivo models. Whether the addition of avibactam to piperacillin enables use of the latter against M. abscessus is unknown Methods We used a recombinant, luminescent M. abscessus to measure the reduction of MIC to meropenem, ampicillin, and piperacillin induced by avibactam. We then used our previously established G. mellonella infection model (Figure 1)1 to evaluate the effect of antimicrobial treatments in vivo. Results Addition of avibactam (4 µg/mL) consistently decreased MIC of ampicillin and piperacillin by 16 and 16–32-fold, respectively, but as expected had no significant effect on meropenem MIC (Figure 2). We inoculated 60 G. mellonella larvae with luminescent M. abscessus on day 0, and treated larvae with meropenem, piperacillin, avibactam alone, or piperacillin combined with avibactam on days 2 and 3. Using IVIS® imaging, we measured infection progression in live infected larvae on day 4. Larvae treated with meropenem and piperacillin–avibactam had significantly lower infection burden compared with untreated controls (P &lt; 0.0001 and P = 0.004, respectively). Piperacillin and avibactam alone had no significant inhibitory effect (Figure 3). Conclusion Our findings suggest that the piperacillin–avibactam combination is effective against M. abscessus infections. This novel combination may hold a great promise for patients with cystic fibrosis suffering from M. abscessus, Pseudomonas aeruginosa, and/or Staphylococcus aureus co-infections. The G. mellonella infection model may be used in future studies to assess the efficacy of various antimicrobials and antimicrobial combinations on M. abscessus, P. aeruginosa, and S. aureus co-infections. Reference 1. Meir M et al. Antimicrob Agents Chemother. 2018. Disclosures All authors: No reported disclosures.

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