scholarly journals Elucidating the mechanism by which synthetic helper peptides sensitize Pseudomonas aeruginosa to multiple antibiotics

2021 ◽  
Vol 17 (9) ◽  
pp. e1009909
Author(s):  
Yushan Xia ◽  
Rubén Cebrián ◽  
Congjuan Xu ◽  
Anne de Jong ◽  
Weihui Wu ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Treatment Strategies ◽  
Infection Model ◽  
Bacterial Cells ◽  
Membrane Phospholipids ◽  
Gram Negative ◽  
Atp Production ◽  
Rapid Spread ◽  
New Treatment ◽  
Multiple Antibiotics

The emergence and rapid spread of multi-drug resistant (MDR) bacteria pose a serious threat to global healthcare. There is an urgent need for new antibacterial substances or new treatment strategies to deal with the infections by MDR bacterial pathogens, especially the Gram-negative pathogens. In this study, we show that a number of synthetic cationic peptides display strong synergistic antimicrobial effects with multiple antibiotics against the Gram-negative pathogen Pseudomonas aeruginosa. We found that an all-D amino acid containing peptide called D-11 increases membrane permeability by attaching to LPS and membrane phospholipids, thereby facilitating the uptake of antibiotics. Subsequently, the peptide can dissipate the proton motive force (PMF) (reduce ATP production and inhibit the activity of efflux pumps), impairs the respiration chain, promote the production of reactive oxygen species (ROS) in bacterial cells and induce intracellular antibiotics accumulation, ultimately resulting in cell death. By using a P. aeruginosa abscess infection model, we demonstrate enhanced therapeutic efficacies of the combination of D-11 with various antibiotics. In addition, we found that the combination of D-11 and azithromycin enhanced the inhibition of biofilm formation and elimination of established biofilms. Our study provides a realistic treatment option for combining close-to-nature synthetic peptide adjuvants with existing antibiotics to combat infections caused by P. aeruginosa.

scholarly journals Efficacy of Humanized Cefiderocol Exposures over 72 Hours against a Diverse Group of Gram-Negative Isolates in the Neutropenic Murine Thigh Infection Model

2018 ◽  
Vol 63 (2) ◽  
pp. e01040-18 ◽  
Author(s):  
Sean M. Stainton ◽  
Marguerite L. Monogue ◽  
Masakatsu Tsuji ◽  
Yoshinori Yamano ◽  
Roger Echols ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Acinetobacter Baumannii ◽  
Infection Model ◽  
Diverse Group ◽  
Gram Negative ◽  
Content Type ◽  
Adaptive Resistance

ABSTRACT Herein, we evaluated sustainability of humanized exposures of cefiderocol in vivo over 72 h against pathogens with cefiderocol MICs of 0.5 to 16 μg/ml in the neutropenic murine thigh model. In Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacteriaceae displaying MICs of 0.5 to 8 μg/ml (n = 11), sustained kill was observed at 72 h among 9 isolates. Postexposure MICs revealed a single 2-dilution increase in one animal compared with controls (1/54 samples, 1.8%) at 72 h. Adaptive resistance during therapy was not observed.

scholarly journals TSPphg Lysin from the Extremophilic Thermus Bacteriophage TSP4 as a Potential Antimicrobial Agent against Both Gram-Negative and Gram-Positive Pathogenic Bacteria

Viruses ◽  
2020 ◽  
Vol 12 (2) ◽  
pp. 192 ◽  
Author(s):  
Feng Wang ◽  
Xinyu Ji ◽  
Qiupeng Li ◽  
Guanling Zhang ◽  
Jiani Peng ◽  
...  
Keyword(s):  
Bacterial Infections ◽  
Pathogenic Bacteria ◽  
Infection Model ◽  
Bacterial Cells ◽  
Skin Damage ◽  
Gram Positive ◽  
Antibiotic Resistant ◽  
Gram Negative

New strategies against antibiotic-resistant bacterial pathogens are urgently needed but are not within reach. Here, we present in vitro and in vivo antimicrobial activity of TSPphg, a novel phage lysin identified from extremophilic Thermus phage TSP4 by sequencing its whole genome. By breaking down the bacterial cells, TSPphg is able to cause bacteria destruction and has shown bactericidal activity against both Gram-negative and Gram-positive pathogenic bacteria, especially antibiotic-resistant strains of Klebsiella pneumoniae, in which the complete elimination and highest reduction in bacterial counts by greater than 6 logs were observed upon 50 μg/mL TSPphg treatment at 37 °C for 1 h. A murine skin infection model further confirmed the in vivo efficacy of TSPphg in removing a highly dangerous and multidrug-resistant Staphylococcus aureus from skin damage and in accelerating wound closure. Together, our findings may offer a therapeutic alternative to help fight bacterial infections in the current age of mounting antibiotic resistance, and to shed light on bacteriophage-based strategies to develop novel anti-infectives.

scholarly journals Cephalosporins target quorum sensing and suppress virulence of Pseudomonas aeruginosa in Caenorhabditis elegans infection model

2020 ◽  
Author(s):  
Lokender Kumar ◽  
Nathanael Brenner ◽  
John Brice ◽  
Judith Klein-Seetharaman ◽  
Susanta K. Sarkar
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Caenorhabditis Elegans ◽  
Quorum Sensing ◽  
Virulence Factors ◽  
Biofilm Formation ◽  
Host Cells ◽  
Infection Model ◽  
Host Immune System ◽  
Bacterial Cells

ABSTRACTPseudomonas aeruginosa utilizes a chemical social networking system referred to as quorum sensing (QS) to strategically co-ordinate the expression of virulence factors and biofilm formation. Virulence attributes damage the host cells, impair the host immune system, and protect bacterial cells from antibiotic attack. Thus, anti-QS agents may act as novel anti-infective therapeutics to treat P. aeruginosa infections. The present study was performed to evaluate the anti-QS, anti-biofilm, and anti-virulence activity of β-lactam antibiotics (carbapenems and cephalosporins) against P. aeruginosa. The anti-QS activity was quantified using Chromobacterium violaceum CV026 as a QS reporter strain. Our results showed that cephalosporins including cefepime (CP), ceftazidime (CF), and ceftriaxone (CT) exhibited potent anti-QS and anti-virulence activities against P. aeruginosa PAO1. These antibiotics significantly impaired motility phenotypes, decreased pyocyanin production, and reduced the biofilm formation by P. aeruginosa PAO1. In the present study, we studied isogenic QS mutants of PAO1: ΔLasR, ΔRhlR, ΔPqsA, and ΔPqsR and found that the levels of virulence factors of antibiotic-treated PAO1 were comparable to QS mutant strains. Molecular docking predicted high binding affinities of cephalosporins for the ligand-binding pocket of QS receptors (CviR, LasR, and PqsR). In addition, our results showed that the anti-microbial activity of aminoglycosides increased in the presence of sub-inhibitory concentrations (sub-MICs) of CP against P. aeruginosa PAO1. Further, utilizing Caenorhabditis elegans as an animal model for the in vivo anti-virulence effects of antibiotics, cephalosporins showed a significant increase in C. elegans survival by suppressing virulence factor production in P. aeruginosa. Thus, our results indicate that cephalosporins might provide a viable anti-virulence therapy in the treatment of infections caused by multi-drug resistant P. aeruginosa.

scholarly journals Role of fatty acids in inflammation, atherosclerosis, metabolic disorders and gout

2021 ◽  
Vol 15 (6) ◽  
pp. 124-129
Author(s):  
M. A. Gromova ◽  
V. V. Tsurko ◽  
O. A. Kislyak ◽  
E. V. Kiseleva
Keyword(s):  
Fatty Acids ◽  
Metabolic Disorders ◽  
Treatment Strategies ◽  
Endothelial Activation ◽  
Transport Systems ◽  
Membrane Phospholipids ◽  
Inflammatory Reactions ◽  
New Treatment ◽  
Urate Crystals

Fatty acids (FA) are present in all types of organisms and play an important role in energy metabolism. The length and number of double bonds in the FA of membrane phospholipids determine the viscosity, the activity of transport systems and enzymes, and also the susceptibility to lipid peroxidation. The review discusses the influence of free unsaturated FAs with short and long chains on various inflammatory mechanisms, including atherosclerosis. It has been shown that FAs can reduce endothelial activation and affect the metabolism of eicosanoids. A new model of fundamental factors determining the variability of the timing, degree and duration of acute inflammatory reactions in the deposition of urate crystals in tissues, in which FAs play an important role is considered, using gout as an example. In the future, the study of FAs will expand the understanding of the pathophysiology of chronic inflammation in various diseases, metabolic disorders and atherosclerosis and enable the development of new treatment strategies. 

scholarly journals Determination of the Dynamically Linked Indices of Fosfomycin for Pseudomonas aeruginosa in the Hollow Fiber Infection Model

2018 ◽  
Vol 62 (6) ◽  
Author(s):  
Arnold Louie ◽  
Michael Maynard ◽  
Brandon Duncanson ◽  
Jocelyn Nole ◽  
Michael Vicchiarelli ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Hollow Fiber ◽  
The United States ◽  
Infection Model ◽  
Combination Regimen ◽  
Bacterial Cells ◽  
Time Curve ◽  
Minimum Concentration ◽  
Content Type

ABSTRACT Fosfomycin is the only expoxide antimicrobial and is currently under development in the United States as an intravenously administered product. We were interested in identifying the exposure indices most closely linked to its ability to kill bacterial cells and to suppress amplification of less susceptible subpopulations. We employed the hollow fiber infection model for this investigation and studied wild-type strain Pseudomonas aeruginosa PAO1. Because of anticipated rapid resistance emergence, we shortened the study duration to 24 h but sampled the system more intensively. Doses of 12 and 18 g/day and schedules of daily administration, administration every 8 h, and administration by continuous infusion for each daily dose were studied. We measured fosfomycin concentrations (by liquid chromatography-tandem mass spectrometry), the total bacterial burden, and the burden of less susceptible isolates. We applied a mathematical model to all the data simultaneously. There was a rapid emergence of resistance with all doses and schedules. Prior to resistance emergence, an initial kill of 2 to 3 log 10 (CFU/ml) was observed. The model demonstrated that the area under the concentration-time curve/MIC ratio was linked to total bacterial kill, while the time that the concentration remained above the MIC (or, equivalently, the minimum concentration/MIC ratio) was linked to resistance suppression. These findings were also seen in other investigations with Enterobacteriaceae ( in vitro systems) and P. aeruginosa (murine system). We conclude that for serious infections with high bacterial burdens, fosfomycin may be of value as a new therapeutic and may be optimized by administering the agent as a continuous or prolonged infusion or by use of a short dosing interval. For indications such as ventilator-associated bacterial pneumonia, it may be prudent to administer fosfomycin as part of a combination regimen.

scholarly journals In VivoActivities of Ceftolozane, a New Cephalosporin, with and without Tazobactam against Pseudomonas aeruginosa and Enterobacteriaceae, Including Strains with Extended-Spectrum β-Lactamases, in the Thighs of Neutropenic Mice

2012 ◽  
Vol 57 (4) ◽  
pp. 1577-1582 ◽  
Author(s):  
W. A. Craig ◽  
D. R. Andes
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Infection Model ◽  
Wild Type ◽  
Gram Negative ◽  
Content Type ◽  
Peak Dose ◽  
Extended Spectrum ◽  
The Impact ◽  
Primary Index

ABSTRACTCeftolozane is a new cephalosporin with potent activity againstPseudomonas aeruginosaandEnterobacteriaceae. A neutropenic murine thigh infection model was used to determine which pharmacokinetic/pharmacodynamic index and magnitude drives the efficacy of ceftolozane with Gram-negative bacilli, to compare the rates ofin vivokilling ofP. aeruginosaby ceftolozane and ceftazidime, and to determine the impact of different ratios of ceftolozane plus tazobactam onEnterobacteriaceaecontaining extended-spectrum β-lactamases (ESBLs). Neutropenic mice had 106.2-7.1CFU/thigh when treated with ceftolozane for 24 h with (i) various doses (3.12 to 1,600 mg/kg) and dosage intervals (3, 6, 12, and 24 h) against twoEnterobacteriaceaestrains, (ii) 0.39 to 800 mg/kg every 6 h for fourEnterobacteriaceaeand fourP. aeruginosastrains, and (iii) 400 or 800 mg/kg with 2:1. 4:1, and 8:1 ratios of tazobactam against fiveEnterobacteriaceaestrains with ESBLs. The pharmacokinetics of ceftolozane at 25, 100, and 400 mg/kg were linear with peak/dose values of 1.0 to 1.4 and half-lives of 12 to 14 min. T>MIC was the primary index driving efficacy. For stasis (1 log kill), T>MIC was 26.3% ± 2.1% (31.6% ± 1.6%) for wild-typeEnterobacteriaceae, 31.1% ± 4.9% (34.8% ± 4.4%) forEnterobacteriaceaewith ESBLs, and 24.0% ± 3.3% (31.5% ± 3.9%) forP. aeruginosa. At 200 mg/kg every 3 h, the rate ofin vivokilling ofP. aeruginosawas faster with ceftolozane than with ceftazidime (−0.34 to −0.41 log10CFU/thigh/h versus −0.21 to −0.24 log10CFU/thigh/h). The 2:1 ratio of ceftolozane with tazobactam was the most potent combination studied. The T>MIC required for ceftolozane is less than with other cephalosporins and may be due to more rapid killing.

scholarly journals Cefepime/tazobactam as a new treatment option for multidrug resistant gram negative bacilli

2019 ◽  
Vol 7 (6) ◽  
pp. 2278
Author(s):  
Roshni Agarwal ◽  
Vaibhav Agarwal ◽  
Anjali Tewari ◽  
Parwati Upadhyay
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Klebsiella Pneumoniae ◽  
Multidrug Resistant ◽  
Diffusion Method ◽  
Resistant Bacteria ◽  
In Vitro Susceptibility ◽  
Gram Negative ◽  
E Coli ◽  
New Treatment

Background: Every time an antibiotic is used, whether appropriately or not, the probability of the development and spread of antibiotic resistant bacteria is increased. Thus, multidrug resistant bacteria particularly ESBL (Extended spectrum β­lactamase), Amp C and carbapenemases producing gram negative bacilli have emerged as a major health problem all over the world. Considering new treatment options as a carbapenems sparing and resistance prevention modality, this study was aimed to know the in vitro susceptibility pattern of Cefepime/Tazobactam (CPM/TZ) in comparison to other β-Lactam/ β-Lactamase inhibitors (BL/BLI) and carbapenems against GNB.Methods: A prospective study was conducted on all clinical samples received for a period of about 1 year. Identification and susceptibility of all isolates was done by Vitek 2 Compact system. Susceptibility of CPM/ TZ was done by disc diffusion method on the basis of CLSI guidelines. Both fermenters (E. coli and Klebsiella pneumoniae) and non-fermenters (Acintobacter baumanii and Pseudomonas aeruginosa) were included in the study.Results: Out of 550 GNB isolates the most common was E. coli (61.8%), Acintobacter baumanii (16%), Klebsiella pneumoniae (14.9%) and Pseudomonas aeruginosa (7.3%). Cefepime/tazobactam had a much higher susceptibility of 68% compared to cefepime (28%). Among the BL/BLI combinations tested cefepime/tazobactam (68%) showed the maximum percentage of susceptibility followed by cefoperazone/sulbactam (61.5%) and piperacillin/tazobactam (57.6%). Amongst all GNB isolates cefepime/tazobactam (68%) sensitivity was very much comparable to imipenem (71.8%) and meropenem (69.6%).Conclusions: CPM/TZ exhibited the best in vitro activity in comparison to the other BL/BLI. This new combination of cefepime/tazobactam appears to be a promising alternative therapeutic option to carbapenems. Clinical studies are needed to confirm this in vitro study result.

scholarly journals Inhibition of Pseudomonas aeruginosa Biofilm Formation with Surface Modified Polymeric Nanoparticles

Pathogens ◽  
2019 ◽  
Vol 8 (2) ◽  
pp. 55 ◽  
Author(s):  
Tyler Flockton ◽  
Logan Schnorbus ◽  
Agustin Araujo ◽  
Jill Adams ◽  
Maryjane Hammel ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Antibiotic Resistance ◽  
Virulence Factors ◽  
Biofilm Formation ◽  
Polymeric Nanoparticles ◽  
Bacterial Pathogen ◽  
Gram Negative ◽  
Treatment Technologies ◽  
New Treatment ◽  
Surface Modified

The gram-negative bacterial pathogen Pseudomonas aeruginosa represents a prominent clinical concern. Due to the observed high levels of antibiotic resistance, copious biofilm formation, and wide array of virulence factors produced by these bacteria, new treatment technologies are required. Here, we present the development of a series of P. aeruginosa LecA-targeted polymeric nanoparticles and demonstrate the anti-adhesion and biofilm inhibitory properties of these constructs.

scholarly journals In Vivo Pharmacodynamic Profiling of Doripenem against Pseudomonas aeruginosa by Simulating Human Exposures

2008 ◽  
Vol 52 (7) ◽  
pp. 2497-2502 ◽  
Author(s):  
Aryun Kim ◽  
Mary Anne Banevicius ◽  
David P. Nicolau
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Broad Spectrum ◽  
Intravenous Infusion ◽  
Infection Model ◽  
Gram Negative ◽  
Wide Range ◽  
Bactericidal Effects ◽  
Dosing Regimens ◽  
Infusion Regimen

ABSTRACT Doripenem is a new broad-spectrum carbapenem with activity against a range of gram-negative pathogens, including nonfermenting bacteria such as Pseudomonas aeruginosa. The objective of this study was to evaluate simulated human exposures to doripenem using a neutropenic murine thigh infection model against 24 clinical P. aeruginosa isolates with a wide range of MICs. Dosing regimens in mice were designed to approximate the free time above MIC (fT>MIC) observed with 500 mg doripenem every 8 h given as either a 1-h or 4-h intravenous infusion in humans. Maximal antibacterial killing was associated with doripenem exposures of ≥40% fT>MIC; bacteriostatic effects were noted at ≈20% fT>MIC. The simulated 1-h infusion provided bactericidal effects for isolates with MICs of ≤2 μg/ml, while variable killing was noted for isolates with MICs of 4 to 8 μg/ml and regrowth for isolates with an MIC of 16 μg/ml. The 4-h infusion regimen displayed similar killing for isolates with MICs of ≤2 μg/ml and enhanced activity for two of the four isolates with an MIC of 4 μg/ml. Given that the 4-h regimen yields negligible fT>MIC for MICs of ≥8 μg/ml, regrowth was generally observed. Simulated doses of 500 mg doripenem every 8 h infused over 1 h demonstrated antibacterial killing for P. aeruginosa isolates with MICs of 0.125 to 8 μg/ml. Exposures of ≥40% fT>MIC resulted in the most pronounced bactericidal effects, while killing was variable for 20 to 30% fT>MIC. Infusing doses over 4 h enhanced efficacy against selected pseudomonal isolates with an MIC of 4 μg/ml.

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