Rhesus θ-defensin-1 (RTD-1) exhibits in vitro and in vivo activity against cystic fibrosis strains of Pseudomonas aeruginosa.
J Antimicrob Chemother
; 71(1): 181-8, 2016 Jan.
Article
en En
| MEDLINE
| ID: mdl-26433781
ABSTRACT
OBJECTIVES:
Chronic endobronchial infections with Pseudomonas aeruginosa contribute to bronchiectasis and progressive loss of lung function in patients with cystic fibrosis. This study aimed to evaluate the therapeutic potential of a novel macrocyclic peptide, rhesus θ-defensin-1 (RTD-1), by characterizing its in vitro antipseudomonal activity and in vivo efficacy in a murine model of chronic Pseudomonas lung infection.METHODS:
Antibacterial testing of RTD-1 was performed on 41 clinical isolates of P. aeruginosa obtained from cystic fibrosis patients. MIC, MBC, time-kill and post-antibiotic effects were evaluated following CLSI-recommended methodology, but using anion-depleted Mueller-Hinton broth. RTD-1 was nebulized daily for 7 days to cystic fibrosis transmembrane conductance regulator (CFTR) F508del-homozygous mice infected using the agar bead model of chronic P. aeruginosa lung infection. In vivo activity was evaluated by change in lung bacterial burden, airway leucocytes and body weight.RESULTS:
RTD-1 exhibited potent in vitro bactericidal activity against mucoid and non-mucoid strains of P. aeruginosa (MIC90â=â8 mg/L). Cross-resistance was not observed when tested against MDR and colistin-resistant isolates. Time-kill studies indicated very rapid, concentration-dependent bactericidal activity of RTD-1 with ≥3 log10 cfu/mL reductions at concentrations ≥4× MIC. No post-antibiotic effect was observed. In vivo, nebulized treatment with RTD-1 significantly decreased lung P. aeruginosa burden (mean difference of -1.30 log10 cfu; Pâ=â0.0061), airway leucocytes (mean difference of -0.37 log10; Pâ=â0.0012) and weight loss (mean difference of -12.62% at day 7; Pâ<â0.05) when compared with controls.CONCLUSIONS:
This study suggests that RTD-1 is a promising potential therapeutic agent for cystic fibrosis airway disease.
Texto completo:
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Banco de datos:
MEDLINE
Asunto principal:
Pseudomonas aeruginosa
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Infecciones por Pseudomonas
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Defensinas
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Macaca mulatta
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Antibacterianos
Límite:
Animals
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Humans
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Male
Idioma:
En
Año:
2016
Tipo del documento:
Article