Activity of AMP2041 against human and animal multidrug resistant Pseudomonas aeruginosa clinical isolates

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.

Structure–Activity Study, Characterization, and Mechanism of Action of an Antimicrobial Peptoid D2 and Its d- and l-Peptide Analogues

“…The peptoid D2 showed slower killing kinetics compared to B1 and antimicrobial peptide and peptoid analogues of B1 . Finally, another peptide, AMP2041, showed LD 90 values of 0.5–8 µg/mL against P. aeruginosa strains derived from dog otitis [22].…”

Antimicrobial resistance patterns of Pseudomonas aeruginosa isolated from canine clinical cases at a veterinary academic hospital in South Africa

“…However, given that P. aeruginosa is a secondary pathogen, more clinical and laboratory information is needed to determine the significance of these results (Weese et al 2019 ). Although the presence of P. aeruginosa at these body sites could be attributed mainly to the increased sensitivity to infection because of the easy access (Cabassi et al 2017 ), early diagnosis and implementation of the correct treatment are still important for improved prognosis (Marza et al 2006 ).…”

Determination of minimum inhibitory concentrations for silver sulfadiazine and other topical antimicrobial agents against strains of Pseudomonas aeruginosa isolated from canine otitis externa

“…In addition, they frequently develop resistance to antimicrobial agents considered to be the empirical treatments of choice, notably fluoroquinolones and aminoglycosides . Resistant phenotypes are frequently isolated from dogs, and multidrug‐resistant P. aeruginosa (MDPA) strains are particularly common in dogs suffering from otitis . Active ingredients for topical treatment of otitis externa are typically chosen empirically, using clinical criteria and cytological evaluation .…”