Abstract
BackgroundAntimicrobial resistance is a growing threat to public health. Pseudomonas aeruginosa is a relevant pathogen causing human and animal infections, frequently displaying high levels of resistance to commonly used antimicrobials. The increasing difficulty to develop new effective antibiotics have discouraged investment in this area and only a few new antibiotics are currently under development. An approach to overcome antibiotic resistance could be based on antimicrobial peptides since they offer advantages over currently used microbicides.MethodsThe antimicrobial activity of the synthetic peptide AMP2041 was evaluated against 49 P. aeruginosa clinical strains with high levels of antimicrobial resistance, isolated from humans (n = 19) and animals (n = 30). In vitro activity was evaluated by a microdilution assay for lethal dose 90% (LD90), while the activity over time was performed by time-kill assay with 12.5 µg/ml of AMP2014. Evidences for a direct membrane damage were investigated on P. aeruginosa ATCC 27853 reference strain, on animal isolate PA-VET 38 and on human isolate PA-H 24 by propidium iodide and on P. aeruginosa ATCC 27853 by scanning electron microscopy.ResultsAMP2041 showed a dose-dependent activity, with a mean (SEM) LD90 of 1.69 and 3.3 µg/ml for animal and human strains, respectively. AMP2041 showed microbicidal activity on P. aeruginosa isolates from a patient with cystic fibrosis (CF) and resistance increased from first infection isolate (LD90 = 0.3 μg/ml) to the mucoid phenotype (LD90 = 10.4 μg/ml). The time-kill assay showed a time-dependent bactericidal effect of AMP2041 and LD90 was reached within 20 min for all the strains. The stain-dead assay showed an increasing of membrane permeabilization and SEM analysis revealed holes, dents and bursts throughout bacterial cell wall after 30 min of incubation with AMP2041.ConclusionsThe obtained results assessed for the first time the good antimicrobial activity of AMP2041 on P. aeruginosa strains of human origin, including those deriving from a CF patient. We confirmed the excellent antimicrobial activity of AMP2041 on P. aeruginosa strains derived from dog otitis. We also assessed that AMP2041 antimicrobial activity is linked to changes of the P. aeruginosa cell wall morphology and to the increasing of membrane permeability.
Highlights
Antimicrobial resistance is a growing threat to public health
A review of studies reporting on multi-drug resistant (MDR), extensively-drug resistant (XDR) and pan-drug resistant (PDR) P. aeruginosa infections revealed that aminoglycosides, antipseudomonal penicillins, cephalosporins, carbapenems and fluoroquinolones [4] have become ineffective as first line agents
The aim of the present work was to evaluate the antimicrobial activity of AMP2041 on different MDR, PDR and XDR P. aeruginosa clinical isolates of human origin, including five different phenotypes of P. aeruginosa derived from a single patient with cystic fibrosis, and on clinical MDR P. aeruginosa clinical isolates deriving from animals, mainly dogs with otitis
Summary
Antimicrobial resistance is a growing threat to public health. Pseudomonas aeruginosa is a relevant pathogen causing human and animal infections, frequently displaying high levels of resistance to commonly used antimicrobials. The spread of antimicrobial resistance increase human and animal health hazard worldwide, makes mandatory the investigation of novel approaches to cover the therapeutic shortfall. In this view, one of the actions put forward in the European Commission Action Plan is to develop effective antimicrobials or alternatives for treatment of human and animal infections and to reinforce research to develop innovative means to combat antimicrobial resistance [6]. Antimicrobial peptides offer potential advantages over currently used classes of drugs They may counteract pathogenic challenge by rapid, broad spectrum, microbicidal activity [7], targeting multiple pathogens with one treatment. Antimicrobial peptides could be potentially used in conjunction with conventional antibiotics as part of a “combination therapy” to create an additive or synergistic effect
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