TY - JOUR
T1 - Activity of innate antimicrobial peptides and ivacaftor against clinical cystic fibrosis respiratory pathogens
AU - Payne, Joanna E
AU - Dubois, Alice V
AU - Ingram, Rebecca J
AU - Weldon, Sinead
AU - Taggart, Clifford C
AU - Elborn, J Stuart
AU - Tunney, Michael M
N1 - Copyright © 2017 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.
PY - 2017/9/1
Y1 - 2017/9/1
N2 - There is a clear need for new antimicrobials to improve current treatment of chronic lung infection in people with cystic fibrosis (CF). This study determined the activities of antimicrobial peptides (AMPs) and ivacaftor, a novel CF transmembrane conductance regulator potentiator, for CF treatment. Antimicrobial activities of AMPs [LL37, human β-defensins (HβD) 1-4 and SLPI] and ivacaftor against clinical respiratory isolates (Pseudomonas aeruginosa, Staphylococcus aureus, Streptococcus spp., Achromobacter spp. and Stenotrophomonas maltophilia) were determined using radial diffusion and time-kill assays, respectively. Synergy of LL37 and ivacaftor with tobramycin was determined by time-kill, with in vivo activity of ivacaftor and tobramycin compared using a murine infection model. LL37 and HβD3 were the most active AMPs tested, with MICs ranging from 3.2- ≥ 200 mg/L and 4.8- ≥ 200 mg/L, respectively, except for Achromobacter that was resistant. HβD1 and SLPI demonstrated no antimicrobial activity. LL37 demonstrated synergy with tobramycin against 4/5 S. aureus and 2/5 Streptococcus spp. isolates. Ivacaftor demonstrated bactericidal activity against Streptococcus spp. (mean log10 decrease 3.31 CFU/mL) and bacteriostatic activity against S. aureus (mean log10 change 0.13 CFU/mL), but no activity against other genera. Moreover, ivacaftor demonstrated synergy with tobramycin, with mean log10 decreases of 5.72 CFU/mL and 5.53 CFU/mL at 24 h for S. aureus and Streptococcus spp., respectively. Ivacaftor demonstrated immunomodulatory but no antimicrobial activity in a P. aeruginosa in vivo murine infection model. Following further modulation to enhance activity, AMPs and ivacaftor offer real potential as therapeutics to augment antibiotic therapy of respiratory infection in CF.
AB - There is a clear need for new antimicrobials to improve current treatment of chronic lung infection in people with cystic fibrosis (CF). This study determined the activities of antimicrobial peptides (AMPs) and ivacaftor, a novel CF transmembrane conductance regulator potentiator, for CF treatment. Antimicrobial activities of AMPs [LL37, human β-defensins (HβD) 1-4 and SLPI] and ivacaftor against clinical respiratory isolates (Pseudomonas aeruginosa, Staphylococcus aureus, Streptococcus spp., Achromobacter spp. and Stenotrophomonas maltophilia) were determined using radial diffusion and time-kill assays, respectively. Synergy of LL37 and ivacaftor with tobramycin was determined by time-kill, with in vivo activity of ivacaftor and tobramycin compared using a murine infection model. LL37 and HβD3 were the most active AMPs tested, with MICs ranging from 3.2- ≥ 200 mg/L and 4.8- ≥ 200 mg/L, respectively, except for Achromobacter that was resistant. HβD1 and SLPI demonstrated no antimicrobial activity. LL37 demonstrated synergy with tobramycin against 4/5 S. aureus and 2/5 Streptococcus spp. isolates. Ivacaftor demonstrated bactericidal activity against Streptococcus spp. (mean log10 decrease 3.31 CFU/mL) and bacteriostatic activity against S. aureus (mean log10 change 0.13 CFU/mL), but no activity against other genera. Moreover, ivacaftor demonstrated synergy with tobramycin, with mean log10 decreases of 5.72 CFU/mL and 5.53 CFU/mL at 24 h for S. aureus and Streptococcus spp., respectively. Ivacaftor demonstrated immunomodulatory but no antimicrobial activity in a P. aeruginosa in vivo murine infection model. Following further modulation to enhance activity, AMPs and ivacaftor offer real potential as therapeutics to augment antibiotic therapy of respiratory infection in CF.
KW - Journal Article
U2 - 10.1016/j.ijantimicag.2017.04.014
DO - 10.1016/j.ijantimicag.2017.04.014
M3 - Article
C2 - 28666755
VL - 50
SP - 427
EP - 435
JO - International Journal of Antimicrobial Agents
JF - International Journal of Antimicrobial Agents
SN - 0924-8579
IS - 3
ER -