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A Drug-Repositioning Screening Identifies Pentetic Acid as a Potential Therapeutic Agent for Suppressing the Elastase-Mediated Virulence of Pseudomonas aeruginosa

Authors
 Mia Gi  ;  Junhui Jeong  ;  Keehoon Lee  ;  Kang-Mu Lee  ;  Masanori Toyofuku  ;  Dong Eun Yong  ;  Sang Sun Yoon  ;  Jae Young Choi 
Citation
 ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Vol.58(12) : 7205-7214, 2014 
Journal Title
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
ISSN
 0066-4804 
Issue Date
2014
MeSH
Administration, Intranasal ; Animals ; Anti-Bacterial Agents/metabolism ; Anti-Bacterial Agents/pharmacology* ; Bacterial Proteins/antagonists & inhibitors* ; Bacterial Proteins/chemistry ; Bacterial Proteins/metabolism ; Biofilms/drug effects ; Biofilms/growth & development ; Cations, Divalent ; Cell Line, Tumor ; Drug Repositioning ; Enzyme Inhibitors/metabolism ; Enzyme Inhibitors/pharmacology* ; Humans ; Iron Chelating Agents/metabolism ; Iron Chelating Agents/pharmacology ; Male ; Manganese/metabolism ; Manganese/pharmacology ; Metalloendopeptidases/antagonists & inhibitors* ; Metalloendopeptidases/chemistry ; Metalloendopeptidases/metabolism ; Mice ; Pentetic Acid/metabolism ; Pentetic Acid/pharmacology* ; Pseudomonas Infections/drug therapy* ; Pseudomonas Infections/microbiology ; Pseudomonas aeruginosa/drug effects* ; Pseudomonas aeruginosa/enzymology ; Pseudomonas aeruginosa/pathogenicity ; Quinolones/metabolism ; Quorum Sensing/drug effects ; Small Molecule Libraries/metabolism ; Small Molecule Libraries/pharmacology ; Virulence ; Zinc/metabolism ; Zinc/pharmacology
Abstract
Pseudomonas aeruginosa, a Gram-negative bacterium of clinical significance, produces elastase as a predominant exoprotease. Here, we screened a library of chemical compounds currently used for human medication and identified diethylene triamine penta-acetic acid (DTPA, pentetic acid) as an agent that suppresses the production of elastase. Elastase activity found in the prototype P. aeruginosa strain PAO1 was significantly decreased when grown with a concentration as low as 20 μM DTPA. Supplementation with Zn2+ or Mn2+ ions restored the suppressive effect of DTPA, suggesting that the DTPA-mediated decrease in elastase activity is associated with ion-chelating activity. In DTPA-treated PAO1 cells, transcription of the elastase-encoding lasB gene and levels of the Pseudomonas quinolone signal (PQS), a molecule that mediates P. aeruginosa quorum sensing (QS), were significantly downregulated, reflecting the potential involvement of the PQS QS system in DTPA-mediated elastase suppression. Biofilm formation was also decreased by DTPA treatment. When A549 alveolar type II-like adenocarcinoma cells were infected with PAO1 cells in the presence of DTPA, A549 cell viability was substantially increased. Furthermore, the intranasal delivery of DTPA to PAO1-infected mice alleviated the pathogenic effects of PAO1 cells in the animals. Together, our results revealed a novel function for a known molecule that may help treat P. aeruginosa airway infection.
Full Text
http://aac.asm.org/content/58/12/7205.long
DOI
10.1128/AAC.03063-14
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Laboratory Medicine (진단검사의학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Microbiology (미생물학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Otorhinolaryngology (이비인후과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Yonsei Biomedical Research Center (연세의생명연구원) > 1. Journal Papers
Yonsei Authors
Gi, Mi A(기미아)
Yong, Dong Eun(용동은) ORCID logo https://orcid.org/0000-0002-1225-8477
Yoon, Sang Sun(윤상선) ORCID logo https://orcid.org/0000-0003-2979-365X
Lee, Kang Mu(이강무) ORCID logo https://orcid.org/0000-0001-7414-5921
Jeong, Jun Hui(정준희)
Choi, Jae Young(최재영) ORCID logo https://orcid.org/0000-0001-9493-3458
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/100297
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