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Abstract
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.
Highlights
Vibrio vulnificus is an opportunistic, Gram-negative, halophilic pathogen (Starks et al, 2000)
We showed that fursultiamine hydrochloride (FTH) inhibits HlyU-regulated toxin genes at the transcriptional level without affecting the expression of hns, which acts as repressor of rtxA1 (Liu et al, 2009)
The current study demonstrates that FTH can effectively inhibit the HlyU-regulated virulence factors RtxA1, VvhA, and phospholipase A2 (plpA2) at the transcriptional level, and significantly reduced the virulence of V. vulnificus by disarming its powerful pore-forming toxins and its ability to kill host cells
Summary
Vibrio vulnificus is an opportunistic, Gram-negative, halophilic pathogen (Starks et al, 2000) It causes necrotizing wound infections, cellulitis, gastroenteritis, and devastating septicemia, with mortality rates up to 50%, especially in immunocompromised subjects (Linkous and Oliver, 1999; Jones and Oliver, 2009), which is one of the highest among foodborne diseases (Mead et al, 1999). V. vulnificus evades the host innate immune system to quickly propagate in the Development of an Antivirulence Agent Against V. vulnificus bloodstream, which causes death within a few days of infection This fast rate of disease progression is attributed to the presence of capsular polysaccharide and repeat-in-toxin (RtxA1), which are both suggested to be inhibitory factors of phagocytosis (Tamplin et al, 1985; Lo et al, 2011). V. vulnificus, an antimicrobial resistant, deadly, opportunistic human pathogen is prevalent in a spatiotemporal manner in estuaries and is considered to be an environmental and clinical burden, posing a major health concern among the foodborne infectious diseases (Siboni et al, 2016; Heng et al, 2017)
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