A Novel Zinc (II) Porphyrin Is Synergistic with PEV2 Bacteriophage against <i>Pseudomonas aeruginosa</i> Infections
<i>Pseudomonas aeruginosa</i> (PsA) is an opportunistic bacterial pathogen that causes life-threatening infections in individuals with compromised immune systems and exacerbates health concerns for those with cystic fibrosis (CF). PsA rapidly develops antibiotic resistance; thus, novel t...
| Main Authors: | , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2023-04-01
|
| Series: | Antibiotics |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2079-6382/12/4/735 |
| _version_ | 1797606641932173312 |
|---|---|
| author | Jessica Geyer Kristen A. Krupa Zachary M. Harris Ying Sun Lokesh Sharma Silvia Würstle Buqu Hu Gail Stanley Govindarajan Rajagopalan Erin Pellot Jonathan L. Koff Jayne B. Robinson |
| author_facet | Jessica Geyer Kristen A. Krupa Zachary M. Harris Ying Sun Lokesh Sharma Silvia Würstle Buqu Hu Gail Stanley Govindarajan Rajagopalan Erin Pellot Jonathan L. Koff Jayne B. Robinson |
| author_sort | Jessica Geyer |
| collection | DOAJ |
| description | <i>Pseudomonas aeruginosa</i> (PsA) is an opportunistic bacterial pathogen that causes life-threatening infections in individuals with compromised immune systems and exacerbates health concerns for those with cystic fibrosis (CF). PsA rapidly develops antibiotic resistance; thus, novel therapeutics are urgently needed to effectively combat this pathogen. Previously, we have shown that a novel cationic Zinc (II) porphyrin (ZnPor) has potent bactericidal activity against planktonic and biofilm-associated PsA cells, and disassembles the biofilm matrix via interactions with eDNA In the present study, we report that ZnPor caused a significant decrease in PsA populations in mouse lungs within an in vivo model of PsA pulmonary infection. Additionally, when combined with an obligately lytic phage PEV2, ZnPor at its minimum inhibitory concentration (MIC) displayed synergy against PsA in an established in vitro lung model resulting in greater protection of H441 lung cells versus either treatment alone. Concentrations above the minimum bactericidal concentration (MBC) of ZnPor were not toxic to H441 cells; however, no synergy was observed. This dose-dependent response is likely due to ZnPor’s antiviral activity, reported herein. Together, these findings show the utility of ZnPor alone, and its synergy with PEV2, which could be a tunable combination used in the treatment of antibiotic-resistant infections. |
| first_indexed | 2024-03-11T05:18:05Z |
| format | Article |
| id | doaj.art-86542ffb76884897a7d2ad93480d244d |
| institution | Directory Open Access Journal |
| issn | 2079-6382 |
| language | English |
| last_indexed | 2024-03-11T05:18:05Z |
| publishDate | 2023-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Antibiotics |
| spelling | doaj.art-86542ffb76884897a7d2ad93480d244d2023-11-17T18:03:15ZengMDPI AGAntibiotics2079-63822023-04-0112473510.3390/antibiotics12040735A Novel Zinc (II) Porphyrin Is Synergistic with PEV2 Bacteriophage against <i>Pseudomonas aeruginosa</i> InfectionsJessica Geyer0Kristen A. Krupa1Zachary M. Harris2Ying Sun3Lokesh Sharma4Silvia Würstle5Buqu Hu6Gail Stanley7Govindarajan Rajagopalan8Erin Pellot9Jonathan L. Koff10Jayne B. Robinson11Department of Biology, University of Dayton, Dayton, OH 45469, USADepartment of Chemical and Materials Engineering, University of Dayton, Dayton, OH 45469, USASection of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520, USASection of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520, USASection of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520, USASection of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520, USASection of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520, USASection of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520, USASection of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520, USADepartment of Biology, University of Dayton, Dayton, OH 45469, USASection of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520, USADepartment of Biology, University of Dayton, Dayton, OH 45469, USA<i>Pseudomonas aeruginosa</i> (PsA) is an opportunistic bacterial pathogen that causes life-threatening infections in individuals with compromised immune systems and exacerbates health concerns for those with cystic fibrosis (CF). PsA rapidly develops antibiotic resistance; thus, novel therapeutics are urgently needed to effectively combat this pathogen. Previously, we have shown that a novel cationic Zinc (II) porphyrin (ZnPor) has potent bactericidal activity against planktonic and biofilm-associated PsA cells, and disassembles the biofilm matrix via interactions with eDNA In the present study, we report that ZnPor caused a significant decrease in PsA populations in mouse lungs within an in vivo model of PsA pulmonary infection. Additionally, when combined with an obligately lytic phage PEV2, ZnPor at its minimum inhibitory concentration (MIC) displayed synergy against PsA in an established in vitro lung model resulting in greater protection of H441 lung cells versus either treatment alone. Concentrations above the minimum bactericidal concentration (MBC) of ZnPor were not toxic to H441 cells; however, no synergy was observed. This dose-dependent response is likely due to ZnPor’s antiviral activity, reported herein. Together, these findings show the utility of ZnPor alone, and its synergy with PEV2, which could be a tunable combination used in the treatment of antibiotic-resistant infections.https://www.mdpi.com/2079-6382/12/4/735<i>Pseudomonas aeruginosa</i>porphyrinphage therapyphage–antibiotic synergy (PAS)biofilmmurine lung model |
| spellingShingle | Jessica Geyer Kristen A. Krupa Zachary M. Harris Ying Sun Lokesh Sharma Silvia Würstle Buqu Hu Gail Stanley Govindarajan Rajagopalan Erin Pellot Jonathan L. Koff Jayne B. Robinson A Novel Zinc (II) Porphyrin Is Synergistic with PEV2 Bacteriophage against <i>Pseudomonas aeruginosa</i> Infections Antibiotics <i>Pseudomonas aeruginosa</i> porphyrin phage therapy phage–antibiotic synergy (PAS) biofilm murine lung model |
| title | A Novel Zinc (II) Porphyrin Is Synergistic with PEV2 Bacteriophage against <i>Pseudomonas aeruginosa</i> Infections |
| title_full | A Novel Zinc (II) Porphyrin Is Synergistic with PEV2 Bacteriophage against <i>Pseudomonas aeruginosa</i> Infections |
| title_fullStr | A Novel Zinc (II) Porphyrin Is Synergistic with PEV2 Bacteriophage against <i>Pseudomonas aeruginosa</i> Infections |
| title_full_unstemmed | A Novel Zinc (II) Porphyrin Is Synergistic with PEV2 Bacteriophage against <i>Pseudomonas aeruginosa</i> Infections |
| title_short | A Novel Zinc (II) Porphyrin Is Synergistic with PEV2 Bacteriophage against <i>Pseudomonas aeruginosa</i> Infections |
| title_sort | novel zinc ii porphyrin is synergistic with pev2 bacteriophage against i pseudomonas aeruginosa i infections |
| topic | <i>Pseudomonas aeruginosa</i> porphyrin phage therapy phage–antibiotic synergy (PAS) biofilm murine lung model |
| url | https://www.mdpi.com/2079-6382/12/4/735 |
| work_keys_str_mv | AT jessicageyer anovelzinciiporphyrinissynergisticwithpev2bacteriophageagainstipseudomonasaeruginosaiinfections AT kristenakrupa anovelzinciiporphyrinissynergisticwithpev2bacteriophageagainstipseudomonasaeruginosaiinfections AT zacharymharris anovelzinciiporphyrinissynergisticwithpev2bacteriophageagainstipseudomonasaeruginosaiinfections AT yingsun anovelzinciiporphyrinissynergisticwithpev2bacteriophageagainstipseudomonasaeruginosaiinfections AT lokeshsharma anovelzinciiporphyrinissynergisticwithpev2bacteriophageagainstipseudomonasaeruginosaiinfections AT silviawurstle anovelzinciiporphyrinissynergisticwithpev2bacteriophageagainstipseudomonasaeruginosaiinfections AT buquhu anovelzinciiporphyrinissynergisticwithpev2bacteriophageagainstipseudomonasaeruginosaiinfections AT gailstanley anovelzinciiporphyrinissynergisticwithpev2bacteriophageagainstipseudomonasaeruginosaiinfections AT govindarajanrajagopalan anovelzinciiporphyrinissynergisticwithpev2bacteriophageagainstipseudomonasaeruginosaiinfections AT erinpellot anovelzinciiporphyrinissynergisticwithpev2bacteriophageagainstipseudomonasaeruginosaiinfections AT jonathanlkoff anovelzinciiporphyrinissynergisticwithpev2bacteriophageagainstipseudomonasaeruginosaiinfections AT jaynebrobinson anovelzinciiporphyrinissynergisticwithpev2bacteriophageagainstipseudomonasaeruginosaiinfections AT jessicageyer novelzinciiporphyrinissynergisticwithpev2bacteriophageagainstipseudomonasaeruginosaiinfections AT kristenakrupa novelzinciiporphyrinissynergisticwithpev2bacteriophageagainstipseudomonasaeruginosaiinfections AT zacharymharris novelzinciiporphyrinissynergisticwithpev2bacteriophageagainstipseudomonasaeruginosaiinfections AT yingsun novelzinciiporphyrinissynergisticwithpev2bacteriophageagainstipseudomonasaeruginosaiinfections AT lokeshsharma novelzinciiporphyrinissynergisticwithpev2bacteriophageagainstipseudomonasaeruginosaiinfections AT silviawurstle novelzinciiporphyrinissynergisticwithpev2bacteriophageagainstipseudomonasaeruginosaiinfections AT buquhu novelzinciiporphyrinissynergisticwithpev2bacteriophageagainstipseudomonasaeruginosaiinfections AT gailstanley novelzinciiporphyrinissynergisticwithpev2bacteriophageagainstipseudomonasaeruginosaiinfections AT govindarajanrajagopalan novelzinciiporphyrinissynergisticwithpev2bacteriophageagainstipseudomonasaeruginosaiinfections AT erinpellot novelzinciiporphyrinissynergisticwithpev2bacteriophageagainstipseudomonasaeruginosaiinfections AT jonathanlkoff novelzinciiporphyrinissynergisticwithpev2bacteriophageagainstipseudomonasaeruginosaiinfections AT jaynebrobinson novelzinciiporphyrinissynergisticwithpev2bacteriophageagainstipseudomonasaeruginosaiinfections |