title: A drug-repositioning screening identifies pentetic acid as a potential therapeutic agent for suppressing the elastase-mediated virulence of Pseudomonas aeruginosa.
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 Zn(2+) or Mn(2+) 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.
authors.affiliation: Department of Otorhinolaryngology, Brain Korea 21 PLUS Project for Medical Science, Seoul, South Korea.
authors.forename: Mia
authors.initials: M
authors.lastname: Gi
authors.affiliation: Department of Otorhinolaryngology, Brain Korea 21 PLUS Project for Medical Science, Seoul, South Korea.
authors.forename: Junhui
authors.initials: J
authors.lastname: Jeong
authors.affiliation: Department of Microbiology and Immunology, Brain Korea 21 PLUS Project for Medical Science, Seoul, South Korea.
authors.forename: Keehoon
authors.initials: K
authors.lastname: Lee
authors.affiliation: Department of Microbiology and Immunology, Brain Korea 21 PLUS Project for Medical Science, Seoul, South Korea.
authors.forename: Kang-Mu
authors.initials: KM
authors.lastname: Lee
authors.affiliation: Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan.
authors.forename: Masanori
authors.initials: M
authors.lastname: Toyofuku
authors.affiliation: Department of Laboratory Medicine, Yonsei University College of Medicine, Seoul, South Korea.
authors.forename: Dong Eun
authors.initials: DE
authors.lastname: Yong
authors.affiliation: Department of Microbiology and Immunology, Brain Korea 21 PLUS Project for Medical Science, Seoul, South Korea Institute for Immunology and Immunological Diseases, Seoul, South Korea sangsun_yoon@yuhs.ac jychoi@yuhs.ac.
authors.forename: Sang Sun
authors.initials: SS
authors.lastname: Yoon
authors.affiliation: Department of Otorhinolaryngology, Brain Korea 21 PLUS Project for Medical Science, Seoul, South Korea sangsun_yoon@yuhs.ac jychoi@yuhs.ac.
authors.forename: Jae Young
authors.initials: JY
authors.lastname: Choi
mesh_terms: D000281:Administration, Intranasal; D000818:Animals; D000900:Anti-Bacterial Agents / Q000378:metabolism / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D018441:Biofilms / Q000187:drug effects / Q000254:growth & development; D002413:Cations, Divalent; D045744:Cell Line, Tumor; D058492:Drug Repositioning; D004791:Enzyme Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D007502:Iron Chelating Agents / Q000378:metabolism / Q000494:pharmacology; D008297:Male; D008345:Manganese / Q000378:metabolism / Q000494:pharmacology; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D051379:Mice; D004369:Pentetic Acid / Q000378:metabolism / Q000494:pharmacology*; D011552:Pseudomonas Infections / Q000188:drug therapy* / Q000382:microbiology; D011550:Pseudomonas aeruginosa / Q000187:drug effects* / Q000201:enzymology / Q000472:pathogenicity; D015363:Quinolones / Q000378:metabolism; D053038:Quorum Sensing / Q000187:drug effects; D054852:Small Molecule Libraries / Q000378:metabolism / Q000494:pharmacology; D014774:Virulence; D015032:Zinc / Q000378:metabolism / Q000494:pharmacology
chemical_list: C407944:2-heptyl-3-hydroxy-4-quinolone; D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D002413:Cations, Divalent; D004791:Enzyme Inhibitors; D007502:Iron Chelating Agents; D015363:Quinolones; D054852:Small Molecule Libraries; D008345:Manganese; D004369:Pentetic Acid; D008666:Metalloendopeptidases; C043859:pseudolysin, Pseudomonas aeruginosa; D015032:Zinc