Characterization of the dispirotripiperazine derivative PDSTP as antibiotic adjuvant and antivirulence compound against Pseudomonas aeruginosa
Pseudomonas aeruginosa is a major human pathogen, able to establish difficult-to-treat infections in immunocompromised and people with cystic fibrosis (CF). The high rate of antibiotic treatment failure is due to its notorious drug resistance, often mediated by the formation of persistent biofilms....
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2024-02-01
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| Series: | Frontiers in Microbiology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fmicb.2024.1357708/full |
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| author | Andrea Bonacorsi Gabriele Trespidi Viola C. Scoffone Samuele Irudal Giulia Barbieri Olga Riabova Natalia Monakhova Vadim Makarov Silvia Buroni |
| author_facet | Andrea Bonacorsi Gabriele Trespidi Viola C. Scoffone Samuele Irudal Giulia Barbieri Olga Riabova Natalia Monakhova Vadim Makarov Silvia Buroni |
| author_sort | Andrea Bonacorsi |
| collection | DOAJ |
| description | Pseudomonas aeruginosa is a major human pathogen, able to establish difficult-to-treat infections in immunocompromised and people with cystic fibrosis (CF). The high rate of antibiotic treatment failure is due to its notorious drug resistance, often mediated by the formation of persistent biofilms. Alternative strategies, capable of overcoming P. aeruginosa resistance, include antivirulence compounds which impair bacterial pathogenesis without exerting a strong selective pressure, and the use of antimicrobial adjuvants that can resensitize drug-resistant bacteria to specific antibiotics. In this work, the dispirotripiperazine derivative PDSTP, already studied as antiviral, was characterized for its activity against P. aeruginosa adhesion to epithelial cells, its antibiotic adjuvant ability and its biofilm inhibitory potential. PDSTP was effective in impairing the adhesion of P. aeruginosa to various immortalized cell lines. Moreover, the combination of clinically relevant antibiotics with the compound led to a remarkable enhancement of the antibiotic efficacy towards multidrug-resistant CF clinical strains. PDSTP-ceftazidime combination maintained its efficacy in vivo in a Galleria mellonella infection model. Finally, the compound showed a promising biofilm inhibitory activity at low concentrations when tested both in vitro and using an ex vivo pig lung model. Altogether, these results validate PDSTP as a promising compound, combining the ability to decrease P. aeruginosa virulence by impairing its adhesion and biofilm formation, with the capability to increase antibiotic efficacy against antibiotic resistant strains. |
| first_indexed | 2024-03-08T00:22:27Z |
| format | Article |
| id | doaj.art-eecec8b29cb24247927d9450f0859610 |
| institution | Directory Open Access Journal |
| issn | 1664-302X |
| language | English |
| last_indexed | 2024-03-08T00:22:27Z |
| publishDate | 2024-02-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Microbiology |
| spelling | doaj.art-eecec8b29cb24247927d9450f08596102024-02-16T04:49:01ZengFrontiers Media S.A.Frontiers in Microbiology1664-302X2024-02-011510.3389/fmicb.2024.13577081357708Characterization of the dispirotripiperazine derivative PDSTP as antibiotic adjuvant and antivirulence compound against Pseudomonas aeruginosaAndrea Bonacorsi0Gabriele Trespidi1Viola C. Scoffone2Samuele Irudal3Giulia Barbieri4Olga Riabova5Natalia Monakhova6Vadim Makarov7Silvia Buroni8Department of Biology and Biotechnology "Lazzaro Spallanzani", University of Pavia, Pavia, ItalyDepartment of Biology and Biotechnology "Lazzaro Spallanzani", University of Pavia, Pavia, ItalyDepartment of Biology and Biotechnology "Lazzaro Spallanzani", University of Pavia, Pavia, ItalyDepartment of Biology and Biotechnology "Lazzaro Spallanzani", University of Pavia, Pavia, ItalyDepartment of Biology and Biotechnology "Lazzaro Spallanzani", University of Pavia, Pavia, ItalyResearch Center of Biotechnology RAS, Moscow, RussiaResearch Center of Biotechnology RAS, Moscow, RussiaResearch Center of Biotechnology RAS, Moscow, RussiaDepartment of Biology and Biotechnology "Lazzaro Spallanzani", University of Pavia, Pavia, ItalyPseudomonas aeruginosa is a major human pathogen, able to establish difficult-to-treat infections in immunocompromised and people with cystic fibrosis (CF). The high rate of antibiotic treatment failure is due to its notorious drug resistance, often mediated by the formation of persistent biofilms. Alternative strategies, capable of overcoming P. aeruginosa resistance, include antivirulence compounds which impair bacterial pathogenesis without exerting a strong selective pressure, and the use of antimicrobial adjuvants that can resensitize drug-resistant bacteria to specific antibiotics. In this work, the dispirotripiperazine derivative PDSTP, already studied as antiviral, was characterized for its activity against P. aeruginosa adhesion to epithelial cells, its antibiotic adjuvant ability and its biofilm inhibitory potential. PDSTP was effective in impairing the adhesion of P. aeruginosa to various immortalized cell lines. Moreover, the combination of clinically relevant antibiotics with the compound led to a remarkable enhancement of the antibiotic efficacy towards multidrug-resistant CF clinical strains. PDSTP-ceftazidime combination maintained its efficacy in vivo in a Galleria mellonella infection model. Finally, the compound showed a promising biofilm inhibitory activity at low concentrations when tested both in vitro and using an ex vivo pig lung model. Altogether, these results validate PDSTP as a promising compound, combining the ability to decrease P. aeruginosa virulence by impairing its adhesion and biofilm formation, with the capability to increase antibiotic efficacy against antibiotic resistant strains.https://www.frontiersin.org/articles/10.3389/fmicb.2024.1357708/fullPseudomonas aeruginosadrug resistanceantibiotic adjuvantcombination therapyantivirulenceantiadhesion |
| spellingShingle | Andrea Bonacorsi Gabriele Trespidi Viola C. Scoffone Samuele Irudal Giulia Barbieri Olga Riabova Natalia Monakhova Vadim Makarov Silvia Buroni Characterization of the dispirotripiperazine derivative PDSTP as antibiotic adjuvant and antivirulence compound against Pseudomonas aeruginosa Frontiers in Microbiology Pseudomonas aeruginosa drug resistance antibiotic adjuvant combination therapy antivirulence antiadhesion |
| title | Characterization of the dispirotripiperazine derivative PDSTP as antibiotic adjuvant and antivirulence compound against Pseudomonas aeruginosa |
| title_full | Characterization of the dispirotripiperazine derivative PDSTP as antibiotic adjuvant and antivirulence compound against Pseudomonas aeruginosa |
| title_fullStr | Characterization of the dispirotripiperazine derivative PDSTP as antibiotic adjuvant and antivirulence compound against Pseudomonas aeruginosa |
| title_full_unstemmed | Characterization of the dispirotripiperazine derivative PDSTP as antibiotic adjuvant and antivirulence compound against Pseudomonas aeruginosa |
| title_short | Characterization of the dispirotripiperazine derivative PDSTP as antibiotic adjuvant and antivirulence compound against Pseudomonas aeruginosa |
| title_sort | characterization of the dispirotripiperazine derivative pdstp as antibiotic adjuvant and antivirulence compound against pseudomonas aeruginosa |
| topic | Pseudomonas aeruginosa drug resistance antibiotic adjuvant combination therapy antivirulence antiadhesion |
| url | https://www.frontiersin.org/articles/10.3389/fmicb.2024.1357708/full |
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