Synergy Screening Identifies a Compound That Selectively Enhances the Antibacterial Activity of Nitric Oxide
Antibiotic resistance poses a serious threat to global health. To reinforce the anti-infective arsenal, many novel therapeutic strategies to fight bacterial infections are being explored. Among them, anti-virulence therapies, which target pathways important for virulence, have attracted much attenti...
| Main Authors: | , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2020-08-01
|
| Series: | Frontiers in Bioengineering and Biotechnology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/article/10.3389/fbioe.2020.01001/full |
| _version_ | 1818503239354548224 |
|---|---|
| author | Wen Kang Chou Mathini Vaikunthan Hendrik V. Schröder A. James Link A. James Link A. James Link Hahn Kim Hahn Kim Mark P. Brynildsen |
| author_facet | Wen Kang Chou Mathini Vaikunthan Hendrik V. Schröder A. James Link A. James Link A. James Link Hahn Kim Hahn Kim Mark P. Brynildsen |
| author_sort | Wen Kang Chou |
| collection | DOAJ |
| description | Antibiotic resistance poses a serious threat to global health. To reinforce the anti-infective arsenal, many novel therapeutic strategies to fight bacterial infections are being explored. Among them, anti-virulence therapies, which target pathways important for virulence, have attracted much attention. Nitric oxide (NO) defense systems have been identified as critical for the pathogenesis of various bacteria, making them an appealing therapeutic target. In this study, we performed chemical screens to identify inhibitors of NO detoxification in Escherichia coli. We found that 2-mercaptobenzothiazole (2-MBT) can potently inhibit cellular detoxification of NO, achieving a level of inhibition that resembled the effect of genetically removing Hmp, the dominant detoxification enzyme under oxygenated conditions. Further analysis revealed that in the presence of NO, 2-MBT impaired the catalysis of Hmp and synthesis of Hmp and other proteins, whereas in its absence there were minimal perturbations to growth and protein synthesis. In addition, by studying the structure-activity relationship of 2-MBT, we found that both sulfur atoms in 2-MBT were vital for its inhibition of NO detoxification. Interestingly, when 2-mercaptothiazole (2-MT), which lacked the benzene ring, was used, differing biological activities were observed, although they too were NO dependent. Specifically, 2-MT could still prohibit NO detoxification, though it did not interfere with Hmp catalysis; rather, it was a stronger inhibitor of protein synthesis and it reduced the transcript levels of hmp, which was not observed with 2-MBT. Overall, these results provide a strong foundation for further exploration of 2-MBT and 2-MT for therapeutic applications. |
| first_indexed | 2024-12-10T21:21:24Z |
| format | Article |
| id | doaj.art-836565320a8d44f6b39a21eff98a15da |
| institution | Directory Open Access Journal |
| issn | 2296-4185 |
| language | English |
| last_indexed | 2024-12-10T21:21:24Z |
| publishDate | 2020-08-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Bioengineering and Biotechnology |
| spelling | doaj.art-836565320a8d44f6b39a21eff98a15da2022-12-22T01:33:07ZengFrontiers Media S.A.Frontiers in Bioengineering and Biotechnology2296-41852020-08-01810.3389/fbioe.2020.01001530958Synergy Screening Identifies a Compound That Selectively Enhances the Antibacterial Activity of Nitric OxideWen Kang Chou0Mathini Vaikunthan1Hendrik V. Schröder2A. James Link3A. James Link4A. James Link5Hahn Kim6Hahn Kim7Mark P. Brynildsen8Department of Chemical and Biological Engineering, Princeton University, Princeton, NJ, United StatesDepartment of Chemical and Biological Engineering, Princeton University, Princeton, NJ, United StatesDepartment of Chemical and Biological Engineering, Princeton University, Princeton, NJ, United StatesDepartment of Chemical and Biological Engineering, Princeton University, Princeton, NJ, United StatesFrick Chemistry Laboratory, Department of Chemistry, Princeton University, Princeton, NJ, United StatesDepartment of Molecular Biology, Princeton University, Princeton, NJ, United StatesFrick Chemistry Laboratory, Department of Chemistry, Princeton University, Princeton, NJ, United StatesSmall Molecule Screening Center, Princeton University, Princeton, NJ, United StatesDepartment of Chemical and Biological Engineering, Princeton University, Princeton, NJ, United StatesAntibiotic resistance poses a serious threat to global health. To reinforce the anti-infective arsenal, many novel therapeutic strategies to fight bacterial infections are being explored. Among them, anti-virulence therapies, which target pathways important for virulence, have attracted much attention. Nitric oxide (NO) defense systems have been identified as critical for the pathogenesis of various bacteria, making them an appealing therapeutic target. In this study, we performed chemical screens to identify inhibitors of NO detoxification in Escherichia coli. We found that 2-mercaptobenzothiazole (2-MBT) can potently inhibit cellular detoxification of NO, achieving a level of inhibition that resembled the effect of genetically removing Hmp, the dominant detoxification enzyme under oxygenated conditions. Further analysis revealed that in the presence of NO, 2-MBT impaired the catalysis of Hmp and synthesis of Hmp and other proteins, whereas in its absence there were minimal perturbations to growth and protein synthesis. In addition, by studying the structure-activity relationship of 2-MBT, we found that both sulfur atoms in 2-MBT were vital for its inhibition of NO detoxification. Interestingly, when 2-mercaptothiazole (2-MT), which lacked the benzene ring, was used, differing biological activities were observed, although they too were NO dependent. Specifically, 2-MT could still prohibit NO detoxification, though it did not interfere with Hmp catalysis; rather, it was a stronger inhibitor of protein synthesis and it reduced the transcript levels of hmp, which was not observed with 2-MBT. Overall, these results provide a strong foundation for further exploration of 2-MBT and 2-MT for therapeutic applications.https://www.frontiersin.org/article/10.3389/fbioe.2020.01001/fullNOHmpthiazolehigh-throughput synergy screeningHTSS |
| spellingShingle | Wen Kang Chou Mathini Vaikunthan Hendrik V. Schröder A. James Link A. James Link A. James Link Hahn Kim Hahn Kim Mark P. Brynildsen Synergy Screening Identifies a Compound That Selectively Enhances the Antibacterial Activity of Nitric Oxide Frontiers in Bioengineering and Biotechnology NO Hmp thiazole high-throughput synergy screening HTSS |
| title | Synergy Screening Identifies a Compound That Selectively Enhances the Antibacterial Activity of Nitric Oxide |
| title_full | Synergy Screening Identifies a Compound That Selectively Enhances the Antibacterial Activity of Nitric Oxide |
| title_fullStr | Synergy Screening Identifies a Compound That Selectively Enhances the Antibacterial Activity of Nitric Oxide |
| title_full_unstemmed | Synergy Screening Identifies a Compound That Selectively Enhances the Antibacterial Activity of Nitric Oxide |
| title_short | Synergy Screening Identifies a Compound That Selectively Enhances the Antibacterial Activity of Nitric Oxide |
| title_sort | synergy screening identifies a compound that selectively enhances the antibacterial activity of nitric oxide |
| topic | NO Hmp thiazole high-throughput synergy screening HTSS |
| url | https://www.frontiersin.org/article/10.3389/fbioe.2020.01001/full |
| work_keys_str_mv | AT wenkangchou synergyscreeningidentifiesacompoundthatselectivelyenhancestheantibacterialactivityofnitricoxide AT mathinivaikunthan synergyscreeningidentifiesacompoundthatselectivelyenhancestheantibacterialactivityofnitricoxide AT hendrikvschroder synergyscreeningidentifiesacompoundthatselectivelyenhancestheantibacterialactivityofnitricoxide AT ajameslink synergyscreeningidentifiesacompoundthatselectivelyenhancestheantibacterialactivityofnitricoxide AT ajameslink synergyscreeningidentifiesacompoundthatselectivelyenhancestheantibacterialactivityofnitricoxide AT ajameslink synergyscreeningidentifiesacompoundthatselectivelyenhancestheantibacterialactivityofnitricoxide AT hahnkim synergyscreeningidentifiesacompoundthatselectivelyenhancestheantibacterialactivityofnitricoxide AT hahnkim synergyscreeningidentifiesacompoundthatselectivelyenhancestheantibacterialactivityofnitricoxide AT markpbrynildsen synergyscreeningidentifiesacompoundthatselectivelyenhancestheantibacterialactivityofnitricoxide |