TY - JOUR
T1 - Therapeutic efficacy of novel antimicrobial peptide AA139-nanomedicines in a multidrug-resistant Klebsiella pneumoniae pneumonia-septicemia model in rats
AU - van der Weide, Hessel
AU - Cossío, Unai
AU - Gracia, Raquel
AU - Te Welscher, Yvonne M
AU - Ten Kate, Marian T
AU - van der Meijden, Aart
AU - Marradi, Marco
AU - Ritsema, Jeffrey A S
AU - Vermeulen-de Jongh, Denise M C
AU - Storm, Gert
AU - Goessens, Wil H F
AU - Loinaz, Iraida
AU - van Nostrum, Cornelus F
AU - Llop, Jordi
AU - Hays, John P
AU - Bakker-Woudenberg, Irma A J M
N1 - Copyright © 2020 American Society for Microbiology.
PY - 2020/8/20
Y1 - 2020/8/20
N2 - Antimicrobial peptides (AMPs) have seen limited clinical use as antimicrobial agents, largely due to issues relating to toxicity, short biological half-life, and lack of efficacy against Gram-negative bacteria. However, the development of novel AMP-nanomedicines, i.e. AMPs entrapped in nanoparticles, has the potential to ameliorate these clinical problems. The authors investigated two novel nanomedicines based on AA139, an AMP currently in development for the treatment of multidrug-resistant Gram-negative infections. AA139 was entrapped in polymeric nanoparticles (PNP) or lipid-core micelles (MCL). The antimicrobial activity of AA139-PNP and AA139-MCL was determined in vitro The biodistribution and limiting doses of AA139-nanomedicines were determined in uninfected rats via endotracheal aerosolization. The early bacterial killing activity of the AA139-nanomedicines in infected lungs was assessed in a rat model of pneumonia-septicemia caused by an extended-spectrum β-lactamase-producing Klebsiella pneumoniae In this model, the therapeutic efficacy was determined by once-daily (q24h) administration over 10 days. Both AA139-nanomedicines showed equivalent in vitro antimicrobial activities (similar to free AA139) and in uninfected rats they exhibited longer residence times in the lungs compared to free AA139 (∼20% longer for AA139-PNP and ∼80% longer for AA139-MCL), as well as reduced toxicity enabling a higher limiting dose. In rats with pneumonia-septicemia, both AA139-nanomedicines showed significantly improved therapeutic efficacy in terms of an extended rat survival time, although survival of all rats was not achieved. These results demonstrate potential advantages that can be achieved using AMP-nanoformulations. AA139-PNP and AA139-MCL may be promising novel therapeutic agents for the treatment of patients suffering from multidrug-resistant Gram-negative pneumonia-septicemia.
AB - Antimicrobial peptides (AMPs) have seen limited clinical use as antimicrobial agents, largely due to issues relating to toxicity, short biological half-life, and lack of efficacy against Gram-negative bacteria. However, the development of novel AMP-nanomedicines, i.e. AMPs entrapped in nanoparticles, has the potential to ameliorate these clinical problems. The authors investigated two novel nanomedicines based on AA139, an AMP currently in development for the treatment of multidrug-resistant Gram-negative infections. AA139 was entrapped in polymeric nanoparticles (PNP) or lipid-core micelles (MCL). The antimicrobial activity of AA139-PNP and AA139-MCL was determined in vitro The biodistribution and limiting doses of AA139-nanomedicines were determined in uninfected rats via endotracheal aerosolization. The early bacterial killing activity of the AA139-nanomedicines in infected lungs was assessed in a rat model of pneumonia-septicemia caused by an extended-spectrum β-lactamase-producing Klebsiella pneumoniae In this model, the therapeutic efficacy was determined by once-daily (q24h) administration over 10 days. Both AA139-nanomedicines showed equivalent in vitro antimicrobial activities (similar to free AA139) and in uninfected rats they exhibited longer residence times in the lungs compared to free AA139 (∼20% longer for AA139-PNP and ∼80% longer for AA139-MCL), as well as reduced toxicity enabling a higher limiting dose. In rats with pneumonia-septicemia, both AA139-nanomedicines showed significantly improved therapeutic efficacy in terms of an extended rat survival time, although survival of all rats was not achieved. These results demonstrate potential advantages that can be achieved using AMP-nanoformulations. AA139-PNP and AA139-MCL may be promising novel therapeutic agents for the treatment of patients suffering from multidrug-resistant Gram-negative pneumonia-septicemia.
KW - Gram-negative bacteria
KW - Klebsiella pneumoniae
KW - antimicrobial peptides
KW - biodistribution
KW - experimental therapeutics
KW - laboratory animals
KW - micelles
KW - nanomedicines
KW - polymeric nanoparticles
U2 - 10.1128/AAC.00517-20
DO - 10.1128/AAC.00517-20
M3 - Article
C2 - 32540976
SN - 0066-4804
VL - 64
JO - Antimicrobial Agents and Chemotherapy
JF - Antimicrobial Agents and Chemotherapy
IS - 9
ER -