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J Antimicrob Chemother. 2016 Jan;71(1):181-8. doi: 10.1093/jac/dkv301. Epub 2015 Oct 3.

Rhesus θ-defensin-1 (RTD-1) exhibits in vitro and in vivo activity against cystic fibrosis strains of Pseudomonas aeruginosa.

Author information

1
School of Pharmacy, University of Southern California, 1985 Zonal Avenue, Los Angeles, CA 90033, USA beringer@usc.edu.
2
School of Pharmacy, University of Southern California, 1985 Zonal Avenue, Los Angeles, CA 90033, USA.
3
Department of Pathology & Laboratory Medicine, Keck School of Medicine, University of Southern California, 2011 Zonal Avenue, Los Angeles, CA 90033, USA.
4
Department of Pediatrics, Massachusetts General Hospital and Harvard Medical School, 275 Cambridge Street, Boston, MA, USA.
5
Department of Pathology & Laboratory Medicine, Keck School of Medicine, University of Southern California, 2011 Zonal Avenue, Los Angeles, CA 90033, USA USC Norris Comprehensive Cancer Center, 1441 Eastlake Avenue, Los Angeles, CA, USA.

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 (MIC90 = 8 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; P = 0.0061), airway leucocytes (mean difference of -0.37 log10; P = 0.0012) and weight loss (mean difference of -12.62% at day 7; P < 0.05) when compared with controls.

CONCLUSIONS:

This study suggests that RTD-1 is a promising potential therapeutic agent for cystic fibrosis airway disease.

PMID:
26433781
PMCID:
PMC5007590
DOI:
10.1093/jac/dkv301
[Indexed for MEDLINE]
Free PMC Article

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