419 The MEK1/2 inhibitor ATR-002 has dual anti-inflammatory and antibacterial effects during S. aureus infection
Objectives/Goals: Novel therapeutics to control Staphylococcus aureus (S. aureus) infections are needed for people with cystic fibrosis (CF, PwCF). In this study, our objective is to determine if the pharmacologic MEK1/2 inhibitor compound ATR-002 can restrict the growth of S. aureus clinical isolat...
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| Format: | Article |
| Language: | English |
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Cambridge University Press
2025-04-01
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| Series: | Journal of Clinical and Translational Science |
| Online Access: | https://www.cambridge.org/core/product/identifier/S2059866124010276/type/journal_article |
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| author | Eryn Zuiker Mithu De Gregory Serpa Matthew E. Long |
| author_facet | Eryn Zuiker Mithu De Gregory Serpa Matthew E. Long |
| author_sort | Eryn Zuiker |
| collection | DOAJ |
| description | Objectives/Goals: Novel therapeutics to control Staphylococcus aureus (S. aureus) infections are needed for people with cystic fibrosis (CF, PwCF). In this study, our objective is to determine if the pharmacologic MEK1/2 inhibitor compound ATR-002 can restrict the growth of S. aureus clinical isolates and modulate infection in a murine model of S. aureus infection. Methods/Study Population: To evaluate the anti-inflammatory effects of ATR-002 on human macrophages, cells were stimulated with TLR2 agonists FSL1 or Pam3CSK4 with a dose range of ATR-002, and secretion of proinflammatory cytokines were measured by ELISA. To determine the direct antibacterial effect of ATR-002, minimum inhibitory concentration (MIC) assays were performed with the community-associated methicillin-resistant S. aureus strain USA300 and 40 S. aureus isolates from PwCF. To validate our results in vivo, mice were provided i.p. treatment with either vehicle, the MEK1/2 inhibitor compound PD0325901 (20 mg/kg), or ATR-002 (10 mg/kg) prior to intranasal infection with 1x10^7 CFU of USA300. Bacterial burdens at 4- and 24-hour post-infection (p.i.) and inflammatory cell recruitment at 24 hours p.i. were quantified. Results/Anticipated Results: Macrophages treated with ATR-002 exhibited a dose-dependent decrease in secretion of proinflammatory cytokines TNF and IL-8 following TLR stimulation. Our studies identified that ATR-002, but not PD0325901 or other MEK1/2 inhibitors, had direct antibacterial effects, and ATR-002 had an MIC range of 8 to above 64 ug/mL on CF S. aureus isolates. In the murine pulmonary infection model, delivery of ATR-002 and PD0325901 significantly prevented infection-induced loss of body mass and decreased neutrophil inflammation. However, when bacterial burdens were quantified 4-hours p.i., only ATR-002 treatment reduced lung bacterial burden compared to vehicle or PD0325901-treated groups. Discussion/Significance of Impact: These results are the first demonstration of the in vivo anti-inflammatory and antibacterial effects of ATR-002. Our results further demonstrate that ATR-002 exhibits direct antibacterial effects across a collection of clinical isolates of S. aureus. Future studies will continue to investigate the therapeutic potential of ATR-002. |
| format | Article |
| id | doaj-art-ae96c7aabddb4585afc881721138b939 |
| institution | Kabale University |
| issn | 2059-8661 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Cambridge University Press |
| record_format | Article |
| series | Journal of Clinical and Translational Science |
| spelling | doaj-art-ae96c7aabddb4585afc881721138b9392025-08-20T03:40:18ZengCambridge University PressJournal of Clinical and Translational Science2059-86612025-04-01912612610.1017/cts.2024.1027419 The MEK1/2 inhibitor ATR-002 has dual anti-inflammatory and antibacterial effects during S. aureus infectionEryn Zuiker0Mithu De1Gregory Serpa2Matthew E. Long3The Ohio State UniversityThe Ohio State UniversityThe Ohio State UniversityThe Ohio State UniversityObjectives/Goals: Novel therapeutics to control Staphylococcus aureus (S. aureus) infections are needed for people with cystic fibrosis (CF, PwCF). In this study, our objective is to determine if the pharmacologic MEK1/2 inhibitor compound ATR-002 can restrict the growth of S. aureus clinical isolates and modulate infection in a murine model of S. aureus infection. Methods/Study Population: To evaluate the anti-inflammatory effects of ATR-002 on human macrophages, cells were stimulated with TLR2 agonists FSL1 or Pam3CSK4 with a dose range of ATR-002, and secretion of proinflammatory cytokines were measured by ELISA. To determine the direct antibacterial effect of ATR-002, minimum inhibitory concentration (MIC) assays were performed with the community-associated methicillin-resistant S. aureus strain USA300 and 40 S. aureus isolates from PwCF. To validate our results in vivo, mice were provided i.p. treatment with either vehicle, the MEK1/2 inhibitor compound PD0325901 (20 mg/kg), or ATR-002 (10 mg/kg) prior to intranasal infection with 1x10^7 CFU of USA300. Bacterial burdens at 4- and 24-hour post-infection (p.i.) and inflammatory cell recruitment at 24 hours p.i. were quantified. Results/Anticipated Results: Macrophages treated with ATR-002 exhibited a dose-dependent decrease in secretion of proinflammatory cytokines TNF and IL-8 following TLR stimulation. Our studies identified that ATR-002, but not PD0325901 or other MEK1/2 inhibitors, had direct antibacterial effects, and ATR-002 had an MIC range of 8 to above 64 ug/mL on CF S. aureus isolates. In the murine pulmonary infection model, delivery of ATR-002 and PD0325901 significantly prevented infection-induced loss of body mass and decreased neutrophil inflammation. However, when bacterial burdens were quantified 4-hours p.i., only ATR-002 treatment reduced lung bacterial burden compared to vehicle or PD0325901-treated groups. Discussion/Significance of Impact: These results are the first demonstration of the in vivo anti-inflammatory and antibacterial effects of ATR-002. Our results further demonstrate that ATR-002 exhibits direct antibacterial effects across a collection of clinical isolates of S. aureus. Future studies will continue to investigate the therapeutic potential of ATR-002.https://www.cambridge.org/core/product/identifier/S2059866124010276/type/journal_article |
| spellingShingle | Eryn Zuiker Mithu De Gregory Serpa Matthew E. Long 419 The MEK1/2 inhibitor ATR-002 has dual anti-inflammatory and antibacterial effects during S. aureus infection Journal of Clinical and Translational Science |
| title | 419 The MEK1/2 inhibitor ATR-002 has dual anti-inflammatory and antibacterial effects during S. aureus infection |
| title_full | 419 The MEK1/2 inhibitor ATR-002 has dual anti-inflammatory and antibacterial effects during S. aureus infection |
| title_fullStr | 419 The MEK1/2 inhibitor ATR-002 has dual anti-inflammatory and antibacterial effects during S. aureus infection |
| title_full_unstemmed | 419 The MEK1/2 inhibitor ATR-002 has dual anti-inflammatory and antibacterial effects during S. aureus infection |
| title_short | 419 The MEK1/2 inhibitor ATR-002 has dual anti-inflammatory and antibacterial effects during S. aureus infection |
| title_sort | 419 the mek1 2 inhibitor atr 002 has dual anti inflammatory and antibacterial effects during s aureus infection |
| url | https://www.cambridge.org/core/product/identifier/S2059866124010276/type/journal_article |
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