TY - JOUR
T1 - AcrAB-TolC Inhibition by Peptide-Conjugated Phosphorodiamidate Morpholino Oligomers Restores Antibiotic Activity in Vitro and in Vivo
AU - Sturge, Carolyn R.
AU - Felder-Scott, Christina F.
AU - Pifer, Reed
AU - Pybus, Christine
AU - Jain, Raksha
AU - Geller, Bruce L.
AU - Greenberg, David E.
N1 - Funding Information:
This work was funded by the National Institutes of Health [AI105980 awarded to D.E.G. and AI111753 awarded to D.E.G. and B.L.G.]. The authors would like to acknowledge Sarepta Therapeutics for synthesis of the PPMOs used in these experiments. Sarepta Therapeutics holds numerous patents on the methods of synthesis and use of PPMOs. The authors would also like to thank Dr. Erdal Toprak (UT Southwestern, Dallas, TX) for providing the Kieo library strains and Dr. Sam Shelburne (MD Anderson Cancer Center, Houston, TX) for his collaboration and access to his clinical isolates.
Publisher Copyright:
© 2019 American Chemical Society.
PY - 2019/8/9
Y1 - 2019/8/9
N2 - Overexpression of bacterial efflux pumps is a driver of increasing antibiotic resistance in Gram-negative pathogens. The AcrAB-TolC efflux pump has been implicated in resistance to a number of important antibiotic classes including fluoroquinolones, macrolides, and β-lactams. Antisense technology, such as peptide-conjugated phosphorodiamidate morpholino oligomers (PPMOs), can be utilized to inhibit expression of efflux pumps and restore susceptibility to antibiotics. Targeting of the AcrAB-TolC components with PPMOs revealed a sequence for acrA, which was the most effective at reducing antibiotic efflux. This acrA-PPMO enhances the antimicrobial effects of the levofloxacin and azithromycin in a panel of clinical Enterobacteriaceae strains. Additionally, acrA-PPMO enhanced azithromycin in vivo in a K. pneumoniae septicemia model. PPMOs targeting the homologous resistance-nodulation-division (RND)-efflux system in P. aeruginosa, MexAB-OprM, also enhanced potency to several classes of antibiotics in a panel of strains and in a cell culture infection model. These data suggest that PPMOs can be used as an adjuvant in antibiotic therapy to increase the efficacy or extend the spectrum of useful antibiotics against a variety of Gram-negative infections.
AB - Overexpression of bacterial efflux pumps is a driver of increasing antibiotic resistance in Gram-negative pathogens. The AcrAB-TolC efflux pump has been implicated in resistance to a number of important antibiotic classes including fluoroquinolones, macrolides, and β-lactams. Antisense technology, such as peptide-conjugated phosphorodiamidate morpholino oligomers (PPMOs), can be utilized to inhibit expression of efflux pumps and restore susceptibility to antibiotics. Targeting of the AcrAB-TolC components with PPMOs revealed a sequence for acrA, which was the most effective at reducing antibiotic efflux. This acrA-PPMO enhances the antimicrobial effects of the levofloxacin and azithromycin in a panel of clinical Enterobacteriaceae strains. Additionally, acrA-PPMO enhanced azithromycin in vivo in a K. pneumoniae septicemia model. PPMOs targeting the homologous resistance-nodulation-division (RND)-efflux system in P. aeruginosa, MexAB-OprM, also enhanced potency to several classes of antibiotics in a panel of strains and in a cell culture infection model. These data suggest that PPMOs can be used as an adjuvant in antibiotic therapy to increase the efficacy or extend the spectrum of useful antibiotics against a variety of Gram-negative infections.
KW - Escherichia coli
KW - Klebsiella pneumoniae
KW - Pseudomonas aeruginosa
KW - antisense
KW - bacterial efflux pumps
KW - peptide-conjugated phosphorodiamidate morpholino oligomers (PPMOs)
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U2 - 10.1021/acsinfecdis.9b00123
DO - 10.1021/acsinfecdis.9b00123
M3 - Article
C2 - 31119935
AN - SCOPUS:85067979410
SN - 2373-8227
VL - 5
SP - 1446
EP - 1455
JO - ACS infectious diseases
JF - ACS infectious diseases
IS - 8
ER -