scholarly journals Repurposing of the tamoxifen metabolites to treat methicillin-resistant Staphylococcus epidermidis and vancomycin-resistant Enterococcus faecalis infections

2021 ◽  
Author(s):  
Andrea Miró Canturri ◽  
Andrea Vila-Domínguez ◽  
Rafael Ayerbe Algaba ◽  
Jerónimo Pachón ◽  
Manuel Enrique Jiménez-Mejías ◽  
...  
Keyword(s):  
Membrane Permeability ◽  
Bactericidal Activity ◽  
Staphylococcus Epidermidis ◽  
Multidrug Resistant ◽  
New Approach ◽  
Methicillin Resistant ◽  
Tamoxifen Metabolites ◽  
Vancomycin Resistant ◽  
Kill Curve ◽  
Time Kill

Repurposing drugs provides a new approach to the fight against multidrug-resistant (MDR) bacteria. We have reported that three major tamoxifen metabolites, N-desmethyltamoxifen (DTAM), 4-hydroxytamoxifen (HTAM) and endoxifen (ENDX), presented bactericidal activity against Acinetobacter baumannii and Escherichia coli. Here, we aimed to analyse the activity of a mixture of the three tamoxifen metabolites against methicillin-resistant Staphylococcus epidermidis (MRSE) and Enterococcus spp. MRSE (n=17) and Enterococcus spp. (E. faecalis n=8, and E. faecium n=10) strains were used. MIC of the mixture of DTAM, HTAM and ENDX, and vancomycin were determined by microdilution assay. The bactericidal activity of the three metabolites together and vancomycin against MRSE (SE385 and SE742) and vancomycin-resistant E. faecalis (EVR1 and EVR2) strains was determined by time-kill curve assays. Finally, changes in membrane permeability of SE742 and EVR1 strains were analyzed using fluorescence assays. MIC50 and MIC90 of tamoxifen metabolites were 1 mg/L for MRSE strains and 2 mg/L for Enterococcus spp. strains. In the time-killing assays, tamoxifen metabolites mixture showed bactericidal activity at 2x and 4xMIC for MRSE (SE385 and SE742) and E. faecalis (EVR1 and EVR2) strains. This antimicrobial activity of tamoxifen metabolites paralleled an increased membrane permeability of SE385 and EVR2 strains. Altogether, these results showed that tamoxifen metabolites presented antibacterial activity against MRSE and vancomycin-resistant E. faecalis, suggesting that tamoxifen metabolites might increase the arsenal of drugs treatment against these bacterial pathogens.

scholarly journals A Time-Kill Assay Study on the Synergistic Bactericidal Activity of Pomegranate Rind Extract and Zn (II) against Methicillin-Resistant Staphylococcus aureus (MRSA), Staphylococcus epidermidis, Escherichia coli, and Pseudomonas aeruginosa

Biomolecules ◽  
2021 ◽  
Vol 11 (12) ◽  
pp. 1889
Author(s):  
Amal Alrashidi ◽  
Mohammed Jafar ◽  
Niamh Higgins ◽  
Ciara Mulligan ◽  
Carmine Varricchio ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Staphylococcus Aureus ◽  
Pseudomonas Aeruginosa ◽  
Antimicrobial Activity ◽  
Bactericidal Activity ◽  
Staphylococcus Epidermidis ◽  
Methicillin Resistant Staphylococcus Aureus ◽  
Synergistic Activity ◽  
Methicillin Resistant ◽  
Time Kill

There is a need for new antimicrobial systems due to increased global resistance to current antimicrobials. Pomegranate rind extract (PRE) and Zn (II) ions both possess a level of antimicrobial activity and work has previously shown that PRE/Zn (II) in combination possesses synergistic activity against Herpes simplex virus and Micrococcus luteus. Here, we determined whether such synergistic activity extended to other, more pathogenic, bacteria. Reference strains of methicillin-resistant Staphylococcus aureus (MRSA), Staphylococcus epidermidis, Escherichia coli, and Pseudomonas aeruginosa were cultured and subjected to challenge by PRE, Zn (II), or PRE + Zn (II), in time-kill assays. Data were obtained independently by two researchers using different PRE preparations. Statistically significant synergistic activity for PRE + Zn (II) was shown for all four bacterial strains tested compared to untreated controls, although the extent of efficacy and timescales varied. Zn (II) exerted activity and at 1 h, it was not possible to distinguish with PRE + Zn (II) combination treatment in all cases. PRE alone showed low activity against all four bacteria. Reproducible synergistic bactericidal activity involving PRE and Zn (II) has been confirmed. Potential mechanisms are discussed. The development of a therapeutic system that possesses demonstrable antimicrobial activity is supported which lends itself particularly to topical delivery applications, for example MRSA infections.

scholarly journals In Vitro and In Vivo Synergistic Activities of Linezolid Combined with Subinhibitory Concentrations of Imipenem against Methicillin-Resistant Staphylococcus aureus

2005 ◽  
Vol 49 (1) ◽  
pp. 45-51 ◽  
Author(s):  
Cédric Jacqueline ◽  
Dominique Navas ◽  
Eric Batard ◽  
Anne-Françoise Miegeville ◽  
Virginie Le Mabecque ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Bactericidal Activity ◽  
Methicillin Resistant ◽  
In Vivo Experiments ◽  
Low Concentrations ◽  
Mrsa Strains ◽  
Kill Curve ◽  
Time Kill

ABSTRACT Indifference or moderate antagonism of linezolid combined with other antibiotics in vitro and in vivo have mainly been reported in the literature. We have assessed the in vitro activities of linezolid, alone or in combination with imipenem, against methicillin-resistant Staphylococcus aureus (MRSA) strains using the dynamic checkerboard and time-kill curve methods. Linezolid and low concentrations of imipenem had a synergistic effect, leading us to evaluate the in vivo antibacterial activity of the combination using the rabbit endocarditis experimental model. Two MRSA strains were used for in vivo experiments: one was a heterogeneous glycopeptide-intermediate clinical S. aureus strain isolated from blood cultures, and the other was the S. aureus COL reference strain. Animals infected with one of two MRSA strains were randomly assigned to one of the following treatments: no treatment (controls), linezolid (simulating a dose in humans of 10 mg/kg of body weight every 12 h), a constant intravenous infusion of imipenem (which allowed the steady-state concentration of about 1/32 the MIC of imipenem for each strain to be reached in serum), or the combination of both treatments. Linezolid and imipenem as monotherapies exhibited no bactericidal activity against either strain. The combination of linezolid plus imipenem showed in vivo bactericidal activity that corresponded to a decrease of at least 4.5 log CFU/g of vegetation compared to the counts for the controls. In conclusion, the combination exhibited synergistic and bactericidal activities against two MRSA strains after 5 days of treatment. The combination of linezolid plus imipenem appears to be promising for the treatment of severe MRSA infections and merits further investigations to explore the mechanism underlying the synergy between the two drugs.

scholarly journals Repurposing of the Tamoxifen Metabolites to Treat Methicillin-Resistant Staphylococcus epidermidis and Vancomycin-Resistant Enterococcus faecalis Infections

2021 ◽  
Author(s):  
Andrea Miró-Canturri ◽  
Andrea Vila-Domínguez ◽  
Marta Caretero-Ledesma ◽  
Rafael Ayerbe-Algaba ◽  
Jerónimo Pachón ◽  
...  
Keyword(s):  
Antibacterial Activity ◽  
Enterococcus Faecalis ◽  
Staphylococcus Epidermidis ◽  
Bacterial Infections ◽  
Therapeutic Strategies ◽  
Vancomycin Resistant Enterococcus ◽  
Methicillin Resistant ◽  
Content Type ◽  
Tamoxifen Metabolites ◽  
Vancomycin Resistant

The development of new antimicrobial therapeutic strategies requires immediate attention to avoid the tens of millions of deaths predicted to occur by 2050 as a result of MDR bacterial infections. In this study, we assessed the antibacterial activity of three major tamoxifen metabolites, N -desmethyltamoxifen (DTAM), 4-hydroxytamoxifen (HTAM), and endoxifen (ENDX), against methicillin-resistant Staphylococcus epidermidis (MRSE) and Enterococcus spp. ( E. faecalis and E. faecium ).

scholarly journals In VitroActivities of LTX-109, a Synthetic Antimicrobial Peptide, against Methicillin-Resistant, Vancomycin-Intermediate, Vancomycin-Resistant, Daptomycin-Nonsusceptible, and Linezolid-Nonsusceptible Staphylococcus aureus

2012 ◽  
Vol 56 (8) ◽  
pp. 4478-4482 ◽  
Author(s):  
Louis D. Saravolatz ◽  
Joan Pawlak ◽  
Leonard Johnson ◽  
Hector Bonilla ◽  
Louis D. Saravolatz ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Antimicrobial Peptide ◽  
Bactericidal Activity ◽  
Antimicrobial Agents ◽  
Methicillin Resistant ◽  
Content Type ◽  
Vancomycin Resistant ◽  
Time Kill ◽  
Dose Dependent

ABSTRACTLTX-109 and eight other antimicrobial agents were evaluated against 155 methicillin-resistantStaphylococcus aureus(MRSA) isolates, including strains resistant to vancomycin and strains with decreased susceptibility to daptomycin and linezolid, by microdilution tests to determine MICs. Time-kill assays were performed against representative MRSA, vancomycin-intermediateS. aureus(VISA), and vancomycin-resistantS. aureus(VRSA) isolates. LTX-109 demonstrated a MIC range of 2 to 4 μg/ml and dose-dependent rapid bactericidal activity againstS. aureus. This activity was not influenced by resistance to other antistaphylococcal agents.

scholarly journals Trans-Cinnamaldehyde Exhibits Synergy with Conventional Antibiotic against Methicillin-Resistant Staphylococcus aureus

2021 ◽  
Vol 22 (5) ◽  
pp. 2752
Author(s):  
Shu Wang ◽  
Ok-Hwa Kang ◽  
Dong-Yeul Kwon
Keyword(s):  
Staphylococcus Aureus ◽  
Methicillin Resistant Staphylococcus Aureus ◽  
Synergistic Effects ◽  
Regulatory Gene ◽  
Western Blot Assay ◽  
Methicillin Resistant ◽  
Wide Range ◽  
Kill Curve ◽  
Conventional Antibiotics ◽  
Time Kill

Methicillin-resistant Staphylococcus aureus (MRSA) is a major nosocomial pathogen worldwide and has acquired multiple resistance to a wide range of antibiotics. Hence, there is a pressing need to explore novel strategies to overcome the increase in antimicrobial resistance. The present study aims to investigate the efficacy and mechanism of plant-derived antimicrobials, trans-cinnamaldehyde (TCA) in decreasing MRSA’s resistance to eight conventional antibiotics. A checkerboard dilution test and time–kill curve assay are used to determine the synergistic effects of TCA combined with the antibiotics. The results indicated that TCA increased the antibacterial activity of the antibiotics by 2-16-fold. To study the mechanism of the synergism, we analyzed the mecA transcription gene and the penicillin-binding protein 2a level of MRSA treated with TCA by quantitative RT-PCR or Western blot assay. The gene transcription and the protein level were significantly inhibited. Additionally, it was verified that TCA can significantly inhibit the biofilm, which is highly resistant to antibiotics. The expression of the biofilm regulatory gene hld of MRSA after TCA treatment was also significantly downregulated. These findings suggest that TCA maybe is an exceptionally potent modulator of antibiotics.

scholarly journals Repurposing of the Tamoxifen Metabolites to Combat Infections by Multidrug-Resistant Gram-Negative Bacilli

Antibiotics ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 336
Author(s):  
Andrea Miró-Canturri ◽  
Rafael Ayerbe-Algaba ◽  
Andrea Vila-Domínguez ◽  
Manuel E. Jiménez-Mejías ◽  
Jerónimo Pachón ◽  
...  
Keyword(s):  
Outer Membrane Proteins ◽  
Bacterial Load ◽  
Drug Repurposing ◽  
Multidrug Resistant ◽  
E Coli ◽  
Immune System Cell ◽  
Tamoxifen Metabolites ◽  
Potential Alternative ◽  
Immunocompetent Mice ◽  
Time Kill

The development of new strategic antimicrobial therapeutic approaches, such as drug repurposing, has become an urgent need. Previously, we reported that tamoxifen presents therapeutic efficacy against multidrug-resistant (MDR) Acinetobacter baumannii, Pseudomonas aeruginosa, and Escherichia coli in experimental infection models by modulating innate immune system cell traffic. The main objective of this study was to analyze the activity of N-desmethyltamoxifen, 4-hydroxytamoxifen, and endoxifen, three major metabolites of tamoxifen, against these pathogens. We showed that immunosuppressed mice infected with A. baumannii, P. aeruginosa, or E. coli in peritoneal sepsis models and treated with tamoxifen at 80 mg/kg/d for three days still reduced the bacterial load in tissues and blood. Moreover, it increased mice survival to 66.7% (for A. baumannii and E. coli) and 16.7% (for P. aeruginosa) when compared with immunocompetent mice. Further, susceptibility and time-kill assays showed that N-desmethyltamoxifen, 4-hydroxytamoxifen, and endoxifen exhibited minimum inhibitory concentration of the 90% of the isolates (MIC90) values of 16 mg/L, and were bactericidal against clinical isolates of A. baumannii and E. coli. This antimicrobial activity of tamoxifen metabolites paralleled an increased membrane permeability of A. baumannii and E. coli without affecting their outer membrane proteins profiles. Together, these data showed that tamoxifen metabolites presented antibacterial activity against MDR A. baumannii and E. coli, and may be a potential alternative for the treatment of infections caused by these two pathogens.

scholarly journals Novel Antibiotic Combinations of Diverse Subclasses for Effective Suppression of Extensively Drug-Resistant Methicillin-Resistant Staphylococcus aureus (MRSA)

2020 ◽  
Vol 2020 ◽  
pp. 1-10
Author(s):  
Shumyila Nasir ◽  
Muhammad Sufyan Vohra ◽  
Danish Gul ◽  
Umm E Swaiba ◽  
Maira Aleem ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Clavulanic Acid ◽  
Antimicrobial Agents ◽  
Methicillin Resistant Staphylococcus Aureus ◽  
Multidrug Resistant ◽  
Methicillin Resistant ◽  
Development Of Resistance ◽  
Amoxicillin Clavulanic Acid ◽  
Combination Antibiotics ◽  
Time Kill

The emergence of multidrug-resistant pathogens such as methicillin-resistant Staphylococcus aureus (MRSA), the chief etiological agent for a range of refractory infections, has rendered all β-lactams ineffective against it. The treatment process is further complicated with the development of resistance to glycopeptides, primary antibiotics for treatment of MRSA. Antibiotic combination therapy with existing antimicrobial agents may provide an immediate treatment option. Minimum inhibitory concentrations (MICs) of 18 different commercially available antibiotics were determined along with their 90 possible pairwise combinations and 64 triple combinations to filter out 5 best combinations. Time-Kill kinetics of these combinations were then analyzed to find collateral bactericidal combinations which were then tested on other randomly selected MRSA isolates. Among the top 5 combinations including levofloxacin-ceftazidime; amoxicillin/clavulanic acid-tobramycin; amoxicillin/clavulanic acid-cephradine; amoxicillin/clavulanic acid-ofloxacin; and piperacillin/tazobactam-tobramycin, three combinations were found to be collaterally effective. Levofloxacin-ceftazidime acted synergistically in 80% of the tested clinical MRSA isolates. First-line β-lactams of lower generations can be used effectively against MRSA infection when used in combination. Antibiotics other than glycopeptides may still work in combination.

scholarly journals In vitro activities of oxazolidinone compounds U100592 and U100766 against Staphylococcus aureus and Staphylococcus epidermidis.

1996 ◽  
Vol 40 (3) ◽  
pp. 799-801 ◽  
Author(s):  
G W Kaatz ◽  
S M Seo
Keyword(s):  
Staphylococcus Aureus ◽  
Staphylococcus Epidermidis ◽  
Inhibitory Activity ◽  
Antimicrobial Agents ◽  
Methicillin Resistant ◽  
Clinical Strains ◽  
Time Kill

The new oxazolidinone antimicrobial agents U100592 and U100766 demonstrated good in vitro inhibitory activity against clinical strains of Staphylococcus aureus and Staphylococcus epidermidis regardless of methicillin susceptibility. Both agents appeared bacteriostatic by time-kill analysis. Stable resistance to low multiples of the MIC of either drug could be produced only in methicillin-resistant S. aureus.

scholarly journals Evaluation of the Bactericidal Activity of Plazomicin and Comparators against Multidrug-Resistant Enterobacteriaceae

2018 ◽  
Vol 62 (8) ◽  
Author(s):  
M. Thwaites ◽  
D. Hall ◽  
D. Shinabarger ◽  
A. W. Serio ◽  
K. M. Krause ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Klebsiella Pneumoniae ◽  
Bactericidal Activity ◽  
Minimum Bactericidal Concentration ◽  
Multidrug Resistant ◽  
Resistance Mechanisms ◽  
Next Generation ◽  
Content Type ◽  
Time Kill

ABSTRACT The next-generation aminoglycoside plazomicin, in development for infections due to multidrug-resistant (MDR) Enterobacteriaceae, was evaluated alongside comparators for bactericidal activity in minimum bactericidal concentration (MBC) and time-kill (TK) assays against MDR Enterobacteriaceae isolates with characterized aminoglycoside and β-lactam resistance mechanisms. Overall, plazomicin and colistin were the most potent, with plazomicin demonstrating an MBC50/90 of 0.5/4 μg/ml and sustained 3-log10 kill against MDR Escherichia coli, Klebsiella pneumoniae, and Enterobacter spp.

scholarly journals Differences in Hospital-Associated Multidrug-Resistant Organisms and Clostridium difficile Rates Using 2-Day versus 3-Day Definitions

2014 ◽  
Vol 35 (11) ◽  
pp. 1417-1420 ◽  
Author(s):  
Adrijana Gombosev ◽  
Salah E. Fouad ◽  
Eric Cui ◽  
Chenghua Cao ◽  
Leah Terpstra ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Clostridium Difficile ◽  
Infection Prevention ◽  
Prevention Programs ◽  
Multidrug Resistant ◽  
Infect Control Hosp ◽  
Methicillin Resistant ◽  
Vancomycin Resistant Enterococci ◽  
Multidrug Resistant Organisms ◽  
Vancomycin Resistant

We surveyed infection prevention programs in 16 hospitals for hospital-associated methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci, extended-spectrum β-lactamase, and multidrug-resistant Acinetobacter acquisition, as well as hospital-associated MRSA bacteremia and Clostridium difficile infection based on defining events as occurring >2 days versus >3 days after admission. The former resulted in significantly higher median rates, ranging from 6.76% to 45.07% higherInfect Control Hosp Epidemiol 2014;35(11):1417–1420

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