Identification of potential antimicrobial targets of Pseudomonas aeruginosa biofilms through a novel screening approach
Identification of potential antimicrobial targets of Pseudomonas aeruginosa biofilms through a novel screening approach
Pseudomonas aeruginosa is an opportunistic pathogen of considerable medical importance, owing to its pronounced antibiotic tolerance and association with cystic fibrosis and other life-threatening diseases. The aim of this study was to highlight the genes responsible for P. aeruginosa biofilm tolerance to antibiotics and thereby identify potential new targets for the development of drugs against biofilm-related infections. By developing a novel screening approach and utilizing a public P. aeruginosa transposon insertion library, several biofilm-relevant genes were identified. The Pf phage gene (PA0720) and flagellin gene (fliC) conferred biofilm-specific tolerance to gentamicin. Compared with the reference biofilms, the biofilms formed by PA0720 and fliC mutants were completely eliminated with a 4-fold-lower gentamicin concentration. Furthermore, the mreC, pprB, coxC, and PA3785 genes were demonstrated to play major roles in enhancing biofilm tolerance to gentamicin. The analysis of biofilm-relevant genes performed in this study provides important novel insights into the understanding of P. aeruginosa antibiotic tolerance, which will facilitate the detection of antibiotic resistance and the development of antibiofilm strategies against P. aeruginosa. IMPORTANCE Pseudomonas aeruginosa is an opportunistic pathogen of high medical importance and is one of the main pathogens responsible for the mortality of patients with cystic fibrosis. In addition to inherited antibiotic resistance, P. aeruginosa can form biofilms, defined as communities of microorganisms embedded in a self-produced matrix of extracellular polymeric substances adhering to each other and/or to a surface. Biofilms protect bacteria from antibiotic treatments and represent a major reason for antibiotic failure in the treatment of chronic infections caused by cystic fibrosis. Therefore, it is crucial to develop new therapeutic strategies aimed at specifically eradicating biofilms. The aim of this study was to generalize a novel screening method for biofilm research and to identify the possible genes involved in P. aeruginosa biofilm tolerance to antibiotics, both of which could improve the understanding of biofilm-related infections and allow for the identification of relevant therapeutic targets for drug development.
FliC, PA0720, PA3785, biofilm formation, biofilm tolerance
Valentin, Jules D.P.
63941168-7e62-40a5-8ec8-c2053974ea12
Altenried, Stefanie
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Varadarajan, Adithi R.
ff277cc5-a4fc-46cd-9410-fda3a909b017
Ahrens, Christian H.
70789dbf-86c6-4725-beca-8dfa4b4e1323
Schreiber, Frank
996cc9b1-c439-4fae-8a46-43b94608d034
Webb, Jeremy S.
ec0a5c4e-86cc-4ae9-b390-7298f5d65f8d
van der Mei, Henny C.
41a13fec-7b1c-41ce-b765-a53e30030662
Ren, Qun
fdc42b84-e0e0-4626-b7dd-0bd1d25619bf
13 April 2023
Valentin, Jules D.P.
63941168-7e62-40a5-8ec8-c2053974ea12
Altenried, Stefanie
80cf5311-3d82-4b9e-855d-727e08fc2ad4
Varadarajan, Adithi R.
ff277cc5-a4fc-46cd-9410-fda3a909b017
Ahrens, Christian H.
70789dbf-86c6-4725-beca-8dfa4b4e1323
Schreiber, Frank
996cc9b1-c439-4fae-8a46-43b94608d034
Webb, Jeremy S.
ec0a5c4e-86cc-4ae9-b390-7298f5d65f8d
van der Mei, Henny C.
41a13fec-7b1c-41ce-b765-a53e30030662
Ren, Qun
fdc42b84-e0e0-4626-b7dd-0bd1d25619bf
Valentin, Jules D.P., Altenried, Stefanie, Varadarajan, Adithi R., Ahrens, Christian H., Schreiber, Frank, Webb, Jeremy S., van der Mei, Henny C. and Ren, Qun
(2023)
Identification of potential antimicrobial targets of Pseudomonas aeruginosa biofilms through a novel screening approach.
Microbiology Spectrum, 11 (2), [e03099-22].
(doi:10.1128/spectrum.03099-22).
Abstract
Pseudomonas aeruginosa is an opportunistic pathogen of considerable medical importance, owing to its pronounced antibiotic tolerance and association with cystic fibrosis and other life-threatening diseases. The aim of this study was to highlight the genes responsible for P. aeruginosa biofilm tolerance to antibiotics and thereby identify potential new targets for the development of drugs against biofilm-related infections. By developing a novel screening approach and utilizing a public P. aeruginosa transposon insertion library, several biofilm-relevant genes were identified. The Pf phage gene (PA0720) and flagellin gene (fliC) conferred biofilm-specific tolerance to gentamicin. Compared with the reference biofilms, the biofilms formed by PA0720 and fliC mutants were completely eliminated with a 4-fold-lower gentamicin concentration. Furthermore, the mreC, pprB, coxC, and PA3785 genes were demonstrated to play major roles in enhancing biofilm tolerance to gentamicin. The analysis of biofilm-relevant genes performed in this study provides important novel insights into the understanding of P. aeruginosa antibiotic tolerance, which will facilitate the detection of antibiotic resistance and the development of antibiofilm strategies against P. aeruginosa. IMPORTANCE Pseudomonas aeruginosa is an opportunistic pathogen of high medical importance and is one of the main pathogens responsible for the mortality of patients with cystic fibrosis. In addition to inherited antibiotic resistance, P. aeruginosa can form biofilms, defined as communities of microorganisms embedded in a self-produced matrix of extracellular polymeric substances adhering to each other and/or to a surface. Biofilms protect bacteria from antibiotic treatments and represent a major reason for antibiotic failure in the treatment of chronic infections caused by cystic fibrosis. Therefore, it is crucial to develop new therapeutic strategies aimed at specifically eradicating biofilms. The aim of this study was to generalize a novel screening method for biofilm research and to identify the possible genes involved in P. aeruginosa biofilm tolerance to antibiotics, both of which could improve the understanding of biofilm-related infections and allow for the identification of relevant therapeutic targets for drug development.
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accepted_Valentin et al_Spectrum Microbiol
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spectrum.03099-22
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Accepted/In Press date: 15 January 2023
e-pub ahead of print date: 13 February 2023
Published date: 13 April 2023
Additional Information:
Funding Information:
This work was financially supported by the Joint Programming Initiative on Antimicrobial Resistance (JPIAMR), the Swiss National Science Foundation grant numbers 40AR40_173611 (to Q.R.) and 156320 and 197391 (to C.H.A.), German Federal Ministry of Education and Research (BMBF, grant #01KI1710), the Netherlands ZonMW grant 547001003, and the UK Medical Research Council (MRC MR/R005621/1). We declare no competing interest.
Publisher Copyright:
Copyright © 2023 Valentin et al.
Keywords:
FliC, PA0720, PA3785, biofilm formation, biofilm tolerance
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Local EPrints ID: 476685
URI: http://eprints.soton.ac.uk/id/eprint/476685
ISSN: 2165-0497
PURE UUID: 0fb4f73e-b4c5-4d1c-b14a-c367d7c87bf3
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Date deposited: 11 May 2023 16:40
Last modified: 06 Jun 2024 01:44
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Contributors
Author:
Jules D.P. Valentin
Author:
Stefanie Altenried
Author:
Adithi R. Varadarajan
Author:
Christian H. Ahrens
Author:
Frank Schreiber
Author:
Henny C. van der Mei
Author:
Qun Ren
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