Identification and Validation of an Antivirulence Agent Targeting HlyU-Regulated Virulence in Vibrio vulnificus
Antimicrobial resistance (AMR) in pathogens is the result of indiscriminate use of antibiotics and consequent metabolic/genetic modulation to evolve survival strategies and clonal-selection in AMR strains. As an alternative to antibiotic treatment, antivirulence strategies are being developed, not o...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2018-05-01
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| Series: | Frontiers in Cellular and Infection Microbiology |
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| Online Access: | http://journal.frontiersin.org/article/10.3389/fcimb.2018.00152/full |
| _version_ | 1819127183772221440 |
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| author | Saba Imdad Akhilesh Kumar Chaurasia Kyeong Kyu Kim |
| author_facet | Saba Imdad Akhilesh Kumar Chaurasia Kyeong Kyu Kim |
| author_sort | Saba Imdad |
| collection | DOAJ |
| description | Antimicrobial resistance (AMR) in pathogens is the result of indiscriminate use of antibiotics and consequent metabolic/genetic modulation to evolve survival strategies and clonal-selection in AMR strains. As an alternative to antibiotic treatment, antivirulence strategies are being developed, not only to combat bacterial pathogenesis, but also to avoid emerging antibiotic resistance. Vibrio vulnificus is a foodborne pathogen that causes gastroenteritis, necrotizing wound infections, and sepsis with a high rate of mortality. Here, we developed an inhibitor-screening reporter platform to target HlyU, a master transcriptional regulator of virulence factors in V. vulnificus by assessing rtxA1 transcription under its control. The inhibitor-screening platform includes wild type and ΔhlyU mutant strains of V. vulnificus harboring the reporter construct PrtxA1::luxCDABE for desired luminescence signal detection and control background luminescence, respectively. Using the inhibitor-screening platform, we identified a small molecule, fursultiamine hydrochloride (FTH), that inhibits the transcription of the highly invasive repeat-in-toxin (rtxA1) and hemolysin (vvhA) along with other HlyU regulated virulence genes. FTH has no cytotoxic effects on either host cells or pathogen at the tested concentrations. FTH rescues host cells from the necrotic cell-death induced by RtxA1 and decreases the hemolytic activity under in vitro conditions. The most important point is that FTH treatment does not induce the antivirulence resistance. Current study validated the antivirulence strategy targeting the HlyU virulence transcription factor and toxin-network of V. vulnificus and demonstrated that FTH, exhibits a potential to inhibit the pathogenesis of deadly, opportunistic human pathogen, V. vulnificus without inducing AMR. |
| first_indexed | 2024-12-22T08:07:53Z |
| format | Article |
| id | doaj.art-22fe2c13a2284dad8cc2dd8b04896d21 |
| institution | Directory Open Access Journal |
| issn | 2235-2988 |
| language | English |
| last_indexed | 2024-12-22T08:07:53Z |
| publishDate | 2018-05-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Cellular and Infection Microbiology |
| spelling | doaj.art-22fe2c13a2284dad8cc2dd8b04896d212022-12-21T18:33:06ZengFrontiers Media S.A.Frontiers in Cellular and Infection Microbiology2235-29882018-05-01810.3389/fcimb.2018.00152355897Identification and Validation of an Antivirulence Agent Targeting HlyU-Regulated Virulence in Vibrio vulnificusSaba ImdadAkhilesh Kumar ChaurasiaKyeong Kyu KimAntimicrobial resistance (AMR) in pathogens is the result of indiscriminate use of antibiotics and consequent metabolic/genetic modulation to evolve survival strategies and clonal-selection in AMR strains. As an alternative to antibiotic treatment, antivirulence strategies are being developed, not only to combat bacterial pathogenesis, but also to avoid emerging antibiotic resistance. Vibrio vulnificus is a foodborne pathogen that causes gastroenteritis, necrotizing wound infections, and sepsis with a high rate of mortality. Here, we developed an inhibitor-screening reporter platform to target HlyU, a master transcriptional regulator of virulence factors in V. vulnificus by assessing rtxA1 transcription under its control. The inhibitor-screening platform includes wild type and ΔhlyU mutant strains of V. vulnificus harboring the reporter construct PrtxA1::luxCDABE for desired luminescence signal detection and control background luminescence, respectively. Using the inhibitor-screening platform, we identified a small molecule, fursultiamine hydrochloride (FTH), that inhibits the transcription of the highly invasive repeat-in-toxin (rtxA1) and hemolysin (vvhA) along with other HlyU regulated virulence genes. FTH has no cytotoxic effects on either host cells or pathogen at the tested concentrations. FTH rescues host cells from the necrotic cell-death induced by RtxA1 and decreases the hemolytic activity under in vitro conditions. The most important point is that FTH treatment does not induce the antivirulence resistance. Current study validated the antivirulence strategy targeting the HlyU virulence transcription factor and toxin-network of V. vulnificus and demonstrated that FTH, exhibits a potential to inhibit the pathogenesis of deadly, opportunistic human pathogen, V. vulnificus without inducing AMR.http://journal.frontiersin.org/article/10.3389/fcimb.2018.00152/fullVibrio vulnificusrtxA1hemolysinhlyUdrug identification and repositioningfursultiamine hydrochloride |
| spellingShingle | Saba Imdad Akhilesh Kumar Chaurasia Kyeong Kyu Kim Identification and Validation of an Antivirulence Agent Targeting HlyU-Regulated Virulence in Vibrio vulnificus Frontiers in Cellular and Infection Microbiology Vibrio vulnificus rtxA1 hemolysin hlyU drug identification and repositioning fursultiamine hydrochloride |
| title | Identification and Validation of an Antivirulence Agent Targeting HlyU-Regulated Virulence in Vibrio vulnificus |
| title_full | Identification and Validation of an Antivirulence Agent Targeting HlyU-Regulated Virulence in Vibrio vulnificus |
| title_fullStr | Identification and Validation of an Antivirulence Agent Targeting HlyU-Regulated Virulence in Vibrio vulnificus |
| title_full_unstemmed | Identification and Validation of an Antivirulence Agent Targeting HlyU-Regulated Virulence in Vibrio vulnificus |
| title_short | Identification and Validation of an Antivirulence Agent Targeting HlyU-Regulated Virulence in Vibrio vulnificus |
| title_sort | identification and validation of an antivirulence agent targeting hlyu regulated virulence in vibrio vulnificus |
| topic | Vibrio vulnificus rtxA1 hemolysin hlyU drug identification and repositioning fursultiamine hydrochloride |
| url | http://journal.frontiersin.org/article/10.3389/fcimb.2018.00152/full |
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