scholarly journals New auranofin analogs with antibacterial properties against Burkholderia clinical isolates

2021 ◽  
Author(s):  
Dustin Maydaniuk ◽  
Bin Wu ◽  
Dang Truong ◽  
Sajani H. Liyanage ◽  
Andrew M. Hogan ◽  
...  
Keyword(s):  
Burkholderia Cepacia ◽  
Burkholderia Pseudomallei ◽  
Galleria Mellonella ◽  
Antibacterial Properties ◽  
Clinical Isolates ◽  
Model Organisms ◽  
Gram Positive Bacteria ◽  
Low Toxicity ◽  
Intrinsic Drug Resistance ◽  
High Concentrations

AbstractBacteria of the genus Burkholderia include pathogenic Burkholderia mallei, Burkholderia pseudomallei and the Burkholderia cepacia complex (Bcc). These Gram-negative pathogens have intrinsic drug resistance, which makes treatment of infections difficult. Bcc affects individuals with cystic fibrosis (CF) and the species B. cenocepacia is associated with one of the worst clinical outcomes. Following the repurposing of auranofin as an antibacterial against Gram-positive bacteria, we previously synthetized auranofin analogs with activity against Gram-negatives. In this work, we show that two auranofin analogs, MS-40S and MS-40, have antibiotic activity against Burkholderia clinical isolates. The compounds are bactericidal against B. cenocepacia and kill stationary-phase cells and persisters without selecting for multistep resistance. Caenorhabditis elegans and Galleria mellonella tolerated high concentrations of MS-40S and MS-40, demonstrating that these compounds have low toxicity in these model organisms. In summary, we show that MS-40 and MS-40S have the potential to be effective therapeutic options to treat Burkholderia infections.

scholarly journals New Auranofin Analogs with Antibacterial Properties against Burkholderia Clinical Isolates

Antibiotics ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 1443
Author(s):  
Dustin Maydaniuk ◽  
Bin Wu ◽  
Dang Truong ◽  
Sajani H. Liyanage ◽  
Andrew M. Hogan ◽  
...  
Keyword(s):  
Burkholderia Cepacia ◽  
Galleria Mellonella ◽  
Therapeutic Potential ◽  
Antibacterial Properties ◽  
Antimicrobial Properties ◽  
Clinical Isolates ◽  
Burkholderia Cepacia Complex ◽  
Model Organisms ◽  
Gram Positive Bacteria ◽  
High Concentrations

Bacteria of the genus Burkholderia include pathogenic Burkholderia mallei, Burkholderia pseudomallei and the Burkholderia cepacia complex (Bcc). These Gram-negative pathogens have intrinsic drug resistance, which makes treatment of infections difficult. Bcc affects individuals with cystic fibrosis (CF) and the species B. cenocepacia is associated with one of the worst clinical outcomes. Following the repurposing of auranofin as an antibacterial against Gram-positive bacteria, we previously synthetized auranofin analogs with activity against Gram-negatives. In this work, we show that two auranofin analogs, MS-40S and MS-40, have antibiotic activity against Burkholderia clinical isolates. The compounds are bactericidal against B. cenocepacia and kill stationary-phase cells and persisters without selecting for multistep resistance. Caenorhabditis elegans and Galleria mellonella tolerated high concentrations of MS-40S and MS-40, demonstrating that these compounds have low toxicity in these model organisms. In summary, we show that MS-40 and MS-40S have antimicrobial properties that warrant further investigations to determine their therapeutic potential against Burkholderia infections.

scholarly journals Identification of Specific and Universal Virulence Factors in Burkholderia cenocepacia Strains by Using Multiple Infection Hosts

2009 ◽  
Vol 77 (9) ◽  
pp. 4102-4110 ◽  
Author(s):  
Susanne Uehlinger ◽  
Stephan Schwager ◽  
Steve P. Bernier ◽  
Kathrin Riedel ◽  
David T. Nguyen ◽  
...  
Keyword(s):  
Virulence Factors ◽  
Burkholderia Cepacia ◽  
Galleria Mellonella ◽  
Burkholderia Cenocepacia ◽  
Model Organisms ◽  
Multiple Infection ◽  
Pathogenic Potential ◽  
The Past ◽  
Infection Models ◽  
Lipopolysaccharide Biosynthesis

ABSTRACT Over the past few decades, strains of the Burkholderia cepacia complex have emerged as important pathogens for patients suffering from cystic fibrosis. Identification of virulence factors and assessment of the pathogenic potential of Burkholderia strains have increased the need for appropriate infection models. In previous studies, different infection hosts, including mammals, nematodes, insects, and plants, have been used. At present, however, the extent to which the virulence factors required to infect different hosts overlap is not known. The aim of this study was to analyze the roles of various virulence factors of two closely related Burkholderia cenocepacia strains, H111 and the epidemic strain K56-2, in a multihost pathogenesis system using four different model organisms, namely, Caenorhabditis elegans, Galleria mellonella, the alfalfa plant, and mice or rats. We demonstrate that most of the identified virulence factors are specific for one of the infection models, and only three factors were found to be essential for full pathogenicity in several hosts: mutants defective in (i) quorum sensing, (ii) siderophore production, and (iii) lipopolysaccharide biosynthesis were attenuated in at least three of the infection models and thus may represent promising targets for the development of novel anti-infectives.

Genetic and pharmacological inactivation of d-alanylation of teichoic acids sensitizes pathogenic enterococci to β-lactams

2019 ◽  
Vol 74 (11) ◽  
pp. 3162-3169 ◽  
Author(s):  
Delphine Coupri ◽  
Aurélie Budin-Verneuil ◽  
Axel Hartke ◽  
Abdellah Benachour ◽  
Loïc Léger ◽  
...  
Keyword(s):  
Galleria Mellonella ◽  
Clinical Isolates ◽  
Drug Resistant ◽  
Combination Therapies ◽  
Therapeutic Approaches ◽  
Teichoic Acids ◽  
Gram Positive Bacteria ◽  
Impact On Survival ◽  
Healthcare Associated

AbstractBackgroundEnterococci intrinsically resistant to cephalosporins represent a major cause of healthcare-associated infections, and the emergence of MDR makes therapeutic approaches particularly challenging.ObjectivesTeichoic acids are cell wall glycopolymers present in Gram-positive bacteria. Teichoic acids can be modified by d-alanylation, which requires four proteins encoded by the dltABCD operon. Our objective was to evaluate the Dlt system as a druggable target to treat enterococcal infections.MethodsThe susceptibility of a d-alanylation-deficient strain of Enterococcus faecalis to β-lactam antibiotics individually and/or in combination was analysed. Moreover, a DltA inhibitor was synthesized to test pharmacological inhibition of d-alanylation in vivo and in host using the animal model Galleria mellonella with different clinical isolates of E. faecalis and Enterococcus faecium.ResultsMost cephalosporins used as mono treatment had no impact on survival of the parental strain, but were slightly lethal for the dltA mutant of E. faecalis. Addition of a very low concentration of amoxicillin significantly increased killing of the dltA mutant under these conditions. The most spectacular effect was obtained with a combination of cefotaxime (1 mg/L) and amoxicillin (0.03 mg/L). In the presence of the inhibitor, the WT strain was as susceptible to this combination treatment as the dltA mutant. This molecule associated with the antibiotics was also effective in killing other E. faecalis clinical isolates and successfully prevented death of Galleria infected with either E. faecalis or E. faecium.ConclusionsThe combined results support the potential usefulness of the Dlt system as a target to potentiate antibiotic combination therapies for the treatment of drug-resistant enterococci.

Antifungal Activity Directed Toward the Cell Wall by 2-Cyclohexylidenhydrazo- 4-Phenyl-Thiazole Against Candida albicans

2019 ◽  
Vol 19 (4) ◽  
pp. 428-438 ◽  
Author(s):  
Nívea P. de Sá ◽  
Ana P. Pôssa ◽  
Pilar Perez ◽  
Jaqueline M.S. Ferreira ◽  
Nayara C. Fonseca ◽  
...  
Keyword(s):  
Cell Wall ◽  
Candida Albicans ◽  
Antifungal Activity ◽  
Mammalian Cells ◽  
C Elegans ◽  
Buccal Epithelial Cells ◽  
Mutant Strains ◽  
Low Toxicity ◽  
High Concentrations ◽  
Mic Value

<p>Background: The increasing incidence of invasive forms of candidiasis and resistance to antifungal therapy leads us to seek new and more effective antifungal compounds. </P><P> Objective: To investigate the antifungal activity and toxicity as well as to evaluate the potential targets of 2- cyclohexylidenhydrazo-4-phenyl-thiazole (CPT) in Candida albicans. </P><P> Methods: The antifungal activity of CPT against the survival of C. albicans was investigated in Caenorhabditis elegans. Additionally, we determined the effect of CPT on the inhibition of C. albicans adhesion capacity to buccal epithelial cells (BECs), the toxicity of CPT in mammalian cells, and the potential targets of CPT in C. albicans. </P><P> Results: CPT exhibited a minimum inhibitory concentration (MIC) value of 0.4-1.9 µg/mL. Furthermore, CPT at high concentrations (>60 x MIC) showed no or low toxicity in HepG2 cells and <1% haemolysis in human erythrocytes. In addition, CPT decreased the adhesion capacity of yeasts to the BECs and prolonged the survival of C. elegans infected with C. albicans. Analysis of CPT-treated cells showed that their cell wall was thinner than that of untreated cells, especially the glucan layer. We found that there was a significantly lower quantity of 1,3-β-D-glucan present in CPT-treated cells than that in untreated cells. Assays performed on several mutant strains showed that the MIC value of CPT was high for its antifungal activity on yeasts with defective 1,3-β-glucan synthase. </P><P> Conclusion: In conclusion, CPT appears to target the cell wall of C. albicans, exhibits low toxicity in mammalian cells, and prolongs the survival of C. elegans infected with C. albicans.</p>

scholarly journals Edible Films from Carrageenan/Orange Essential Oil/Trehalose—Structure, Optical Properties, and Antimicrobial Activity

Polymers ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 332
Author(s):  
Jancikova Simona ◽  
Dordevic Dani ◽  
Sedlacek Petr ◽  
Nejezchlebova Marcela ◽  
Treml Jakub ◽  
...  
Keyword(s):  
Antimicrobial Activity ◽  
Essential Oil ◽  
Antibacterial Properties ◽  
Edible Films ◽  
Attenuated Total Reflectance ◽  
Practical Application ◽  
Film Properties ◽  
Gram Positive Bacteria ◽  
Edible Packaging ◽  
Orange Essential Oil

The research aim was to use orange essential oil and trehalose in a carrageenan matrix to form edible packaging. The edible packaging experimentally produced by casting from an aqueous solution were evaluated by the following analysis: UV-Vis spectrum, transparency value, transmittance, attenuated total reflectance Fourier-Transform spectroscopy (FTIR), scanning electron microscopy (SEM) and antimicrobial activity. The obtained results showed that the combination of orange essential oil with trehalose decreases the transmittance value in the UV and Vis regions (up to 0.14% ± 0.02% at 356 nm), meaning that produced films can act as a UV protector. Most produced films in the research were resistant to Gram-positive bacteria (Staphylococcus aureus subsp. aureus), though most films did not show antibacterial properties against Gram-negative bacteria and yeasts. FTIR and SEM confirmed that both the amount of carrageenan used and the combination with orange essential oil influenced the compatibility of trehalose with the film matrix. The research showed how different combinations of trehalose, orange essential oils and carrageenan can affect edible film properties. These changes represent important information for further research and the possible practical application of these edible matrices.

scholarly journals Designing P. aeruginosa synthetic phages with reduced genomes

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Diana P. Pires ◽  
Rodrigo Monteiro ◽  
Dalila Mil-Homens ◽  
Arsénio Fialho ◽  
Timothy K. Lu ◽  
...  
Keyword(s):  
Galleria Mellonella ◽  
Antibacterial Properties ◽  
Genetically Engineered ◽  
In Vivo Studies ◽  
Infection Model ◽  
Promising Therapeutic Approach ◽  
Genes Encoding ◽  
First Time

AbstractIn the era where antibiotic resistance is considered one of the major worldwide concerns, bacteriophages have emerged as a promising therapeutic approach to deal with this problem. Genetically engineered bacteriophages can enable enhanced anti-bacterial functionalities, but require cloning additional genes into the phage genomes, which might be challenging due to the DNA encapsulation capacity of a phage. To tackle this issue, we designed and assembled for the first time synthetic phages with smaller genomes by knocking out up to 48% of the genes encoding hypothetical proteins from the genome of the newly isolated Pseudomonas aeruginosa phage vB_PaeP_PE3. The antibacterial efficacy of the wild-type and the synthetic phages was assessed in vitro as well as in vivo using a Galleria mellonella infection model. Overall, both in vitro and in vivo studies revealed that the knock-outs made in phage genome do not impair the antibacterial properties of the synthetic phages, indicating that this could be a good strategy to clear space from phage genomes in order to enable the introduction of other genes of interest that can potentiate the future treatment of P. aeruginosa infections.

Preparation of bioactive and antibacterial PMMA-based bone cement by modification with quaternary ammonium and alkoxysilane

2021 ◽  
pp. 088532822110044
Author(s):  
Haiyang Wang ◽  
Toshinari Maeda ◽  
Toshiki Miyazaki
Keyword(s):  
Antibacterial Activity ◽  
Methyl Methacrylate ◽  
Bone Cement ◽  
Setting Time ◽  
Antibacterial Properties ◽  
The Body ◽  
Apatite Formation ◽  
Gram Positive ◽  
E Coli ◽  
Gram Positive Bacteria

Bone cement based on poly(methyl methacrylate) (PMMA) powder and methyl methacrylate (MMA) liquid is a very popular biomaterial used for the fixation of artificial joints. However, there is a risk of this cement loosening from bone because of a lack of bone-bonding bioactivity. Apatite formation in the body environment is a prerequisite for cement bioactivity. Additionally, suppression of infection during implantation is required for bone cements to be successfully introduced into the human body. In this study, we modified PMMA cement with γ-methacryloxypropyltrimetoxysilane and calcium acetate to introduce bioactive properties and 2-( tert-butylamino)ethyl methacrylate (TBAEMA) to provide antibacterial properties. The long-term antibacterial activity is attributed to the copolymerization of TBAEMA and MMA. As the TBAEMA content increased, the setting time increased and the compressive strength decreased. After soaking in simulated body fluid, an apatite layer was detected within 7 days, irrespective of the TBAEMA content. The cement showed better antibacterial activity against Gram-negative E. Coli than Gram-positive bacteria; however, of the Gram-positive bacteria investigated, B. subtilis was more susceptible than S. aureus.

scholarly journals Farnesol-Loaded Liposomes Protect the Epidermis and Dermis from PM2.5-Induced Cutaneous Injury

2021 ◽  
Vol 22 (11) ◽  
pp. 6076
Author(s):  
Yu-Chiuan Wu ◽  
Wei-Yun Chen ◽  
Chun-Yin Chen ◽  
Sheng I. Lee ◽  
Yu-Wen Wang ◽  
...  
Keyword(s):  
Chronic Inflammation ◽  
Water Solubility ◽  
Antibacterial Properties ◽  
Hair Follicles ◽  
Protective Effects ◽  
Cutaneous Injury ◽  
Anti Inflammatory ◽  
High Concentrations ◽  
Acute And Chronic Inflammation

Particulate matter with aerodynamic diameter ≤2.5 μm (PM2.5) increases oxidative stress through free radical generation and incomplete volatilization. In addition to affecting the respiratory system, PM2.5 causes aging- and inflammation-related damage to skin. Farnesol (Farn), a natural benzyl semiterpene, possesses anti-inflammatory, antioxidative, and antibacterial properties. However, because of its poor water solubility and cytotoxicity at high concentrations, the biomedical applications of Farn have been limited. This study examined the deleterious effects of PM2.5 on the epidermis and dermis. In addition, Farn-encapsulated liposomes (Lipo-Farn) and gelatin/HA/xanthan gel containing Lipo-Farn were prepared and applied in vivo to repair and alleviate PM2.5-induced damage and inflammation in skin. The prepared Lipo-Farn was 342 ± 90 nm in diameter with an encapsulation rate of 69%; the encapsulation significantly reduced the cytotoxicity of Farn. Lipo-Farn exhibited a slow-release rate of 35% after 192 h of incubation. The half-maximal inhibitory concentration of PM2.5 was approximately 850 μg/mL, and ≥400 μg/mL PM2.5 significantly increased IL-6 production in skin fibroblasts. Severe impairment in the epidermis and hair follicles and moderate impairment in the dermis were found in the groups treated with post-PM2.5 and continuous subcutaneous injection of PM2.5. Acute and chronic inflammation was observed in the skin in both experimental categories in vivo. Treatment with 4 mM Lipo-Farn largely repaired PM2.5-induced injury in the epidermis and dermis, restored injured hair follicles, and alleviated acute and chronic inflammation induced by PM2.5 in rat skin. In addition, treatment with 4 mM pure Farn and 2 mM Lipo-Farn exerted moderate reparative and anti-inflammatory effects on impaired skin. The findings of the current study indicate the therapeutic and protective effects of Lipo-Farn against various injuries caused by PM2.5 in the pilosebaceous units, epidermis, and dermis of skin.

The epidemiology of central venous catheter-related bloodstream infection in our renal units is changing

2021 ◽  
pp. 112972982199022
Author(s):  
Salvatore Mandolfo ◽  
Adriano Anesi ◽  
Vanina Rognoni
Keyword(s):  
Burkholderia Cepacia ◽  
Present Report ◽  
Statistical Significance ◽  
Bloodstream Infections ◽  
Venous Catheter ◽  
Renal Unit ◽  
Gram Positive ◽  
Gram Negative ◽  
Gram Positive Bacteria ◽  
Over Time

Recent reports have shown an increase in the rate of Gram-negative bacteremia in several settings, including catheter-related bloodstream infections (CRBSI). To analyze if the epidemiology of CRBSI is also changing in hemodialysis patients, we revisited the etiology of CRBSIs in our renal unit over 8 years. During the observed periods, 149 episodes of CRBSIs were reported and the CRBSI incidence rate, ranged between 0.67 and 0.82 episodes/1000 tCVC days. Of these 149 episodes, 84 (56.3%) were due to Gram-positive bacteria, 62 (41.6%) to Gram-negative bacteria, and 3 (2.1%) to polymicrobial flora, no episodes of fungi were found. There was a trend, but not statistically significative, increase over time in the number of Gram-negative CRBSIs among the total CRBSIs, rising from 37.8% in the first period to 41.2% in the second period and to 44.3% in the last period, with a parallel decrease in the percentage of Gram-positive CRBSIs (from 59.5% to 56.9% and subsequently to 54.1%). Between Gram-negative, we reported an intensification of CRBSI due to Enterobacterales, particularly Escherichia coli. Among the Gram-negative, we have isolated germs rarely reported in the literature, such as Burkholderia cepacia, Pantoea agglomerans, and Rhizobium radiobacter. Regarding Gram-positive bacteria, a triplicate incidence of Staphylococcus aureus was reported with MRSA accounting for 42% in the third period. Among the Gram-positive bacteria, we reported two episodes of Kocuria kristinae and two of Bacillus spp. Our data demonstrated that the epidemiology of CRBSI in the same center, will change over time and Gram-negative strains are an increasing cause of CRBSI. The limitation of the present report is that statistical significance has not been reached, probably due to the limited number of CRBSI. New bacteria, both Gram-negative and Gram-positive, are emerging. Collaboration with the Microbiology Department appears essential to an appropriate diagnosis.

scholarly journals Genomic Diversity of Burkholderia pseudomallei Clinical Isolates: Subtractive Hybridization Reveals a Burkholderia mallei-Specific Prophage in B. pseudomallei 1026b

2004 ◽  
Vol 186 (12) ◽  
pp. 3938-3950 ◽  
Author(s):  
David DeShazer
Keyword(s):  
Suppression Subtractive Hybridization ◽  
Burkholderia Pseudomallei ◽  
Genomic Sequence ◽  
Subtractive Hybridization ◽  
Etiologic Agent ◽  
Polyclonal Antiserum ◽  
Genomic Diversity ◽  
Clinical Isolates ◽  
Immunogold Electron Microscopy ◽  
Burkholderia Mallei

ABSTRACT Burkholderia pseudomallei is the etiologic agent of the disease melioidosis and is a category B biological threat agent. The genomic sequence of B. pseudomallei K96243 was recently determined, but little is known about the overall genetic diversity of this species. Suppression subtractive hybridization was employed to assess the genetic variability between two distinct clinical isolates of B. pseudomallei, 1026b and K96243. Numerous mobile genetic elements, including a temperate bacteriophage designated φ1026b, were identified among the 1026b-specific suppression subtractive hybridization products. Bacteriophage φ1026b was spontaneously produced by 1026b, and it had a restricted host range, infecting only Burkholderia mallei. It possessed a noncontractile tail, an isometric head, and a linear 54,865-bp genome. The mosaic nature of the φ1026b genome was revealed by comparison with bacteriophage φE125, a B. mallei-specific bacteriophage produced by Burkholderia thailandensis. The φ1026b genes for DNA packaging, tail morphogenesis, host lysis, integration, and DNA replication were nearly identical to the corresponding genes in φE125. On the other hand, φ1026b genes involved in head morphogenesis were similar to head morphogenesis genes encoded by Pseudomonas putida and Pseudomonas aeruginosa bacteriophages. Consistent with this observation, immunogold electron microscopy demonstrated that polyclonal antiserum against φE125 reacted with the tail of φ1026b but not with the head. The results presented here suggest that B. pseudomallei strains are genetically heterogeneous and that bacteriophages are major contributors to the genomic diversity of this species. The bacteriophage characterized in this study may be a useful diagnostic tool for differentiating B. pseudomallei and B. mallei, two closely related biological threat agents.

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