Inhibition of Pseudomonas aeruginosa Alginate Synthesis by Ebselen Oxide and Its Analogues

Soo Kyoung Kim, Huy X. Ngo, Emily K. Dennis, Nishad Thamban Chandrika, Philip Deshong, Sylvie Garneau-Tsodikova, Vincent T. Lee

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

Pseudomonas aeruginosa is a Gram-negative opportunistic pathogen that is frequently found in the airways of cystic fibrosis (CF) patients due to the dehydrated mucus that collapses the underlying cilia and prevents mucociliary clearance. During this life-long chronic infection, P. aeruginosa cell accumulates mutations that lead to inactivation of the mucA gene that results in the constitutive expression of algD-algA operon and the production of alginate exopolysaccharide. The viscous alginate polysaccharide further occludes the airways of CF patients and serves as a protective matrix to shield P. aeruginosa from host immune cells and antibiotic therapy. Development of inhibitors of alginate production by P. aeruginosa would reduce the negative impact from this viscous polysaccharide. In addition to transcriptional regulation, alginate biosynthesis requires allosteric activation by bis (3′-5′)-cyclic dimeric guanosine monophosphate (c-di-GMP) binding to an Alg44 protein. Previously, we found that ebselen (Eb) and ebselen oxide (EbO) inhibited diguanylate cyclase from synthesizing c-di-GMP. In this study, we show that EbO, Eb, ebsulfur (EbS), and their analogues inhibit alginate production. Eb and EbS can covalently modify the cysteine 98 (C98) residue of Alg44 and prevent its ability to bind c-di-GMP. However, P. aeruginosa with Alg44 C98 substituted with alanine or serine was still inhibited for alginate production by Eb and EbS. Our results indicate that EbO, Eb, and EbS are lead compounds for reducing alginate production by P. aeruginosa. Future development of these inhibitors could provide a potential treatment for CF patients infected with mucoid P. aeruginosa.

Original languageEnglish
Pages (from-to)1713-1726
Number of pages14
JournalACS Infectious Diseases
Volume7
Issue number6
DOIs
StatePublished - Jun 11 2021

Bibliographical note

Funding Information:
This work was supported by startup funds from the College of Pharmacy at the University of Kentucky (S.G.-T.). S.-K.K. acknowledges support from the National Research Foundation of Korea (2018R1A6A3A03011278). V.T.L. acknowledges support from the Cystic Fibrosis Foundation (Lee16G0) and National Institutes of Health (R01-AI110740).

Publisher Copyright:
© 2021 American Chemical Society.

Keywords

  • Alg44
  • Pseudomonas aeruginosa
  • alginate
  • cystic fibrosis
  • inhibitors

ASJC Scopus subject areas

  • Infectious Diseases

Fingerprint

Dive into the research topics of 'Inhibition of Pseudomonas aeruginosa Alginate Synthesis by Ebselen Oxide and Its Analogues'. Together they form a unique fingerprint.

Cite this