Abstract
Society faces huge challenges, as a large number of bacteria have developed resistance towards many or all of the antibiotics currently available. Novel strategies that can help solve this problem are urgently needed. One such strategy is to target bacterial virulence, the ability to cause disease e.g., by inhibition of type III secretion systems (T3SSs) utilized by many clinically relevant gram-negative pathogens. Many of the antibiotics used today originate from natural sources. In contrast, most virulence-blocking compounds towards the T3SS identified so far are small organic molecules. A recent high-throughput screening of a prefractionated natural product library identified the resveratrol tetramer (-)-hopeaphenol as an inhibitor of the T3SS in Yersinia pseudotuberculosis. In this study we have investigated the virulence blocking properties of (-)-hopeaphenol in three different gram-negative bacteria. (-)-Hopeaphenol was found to have micromolar activity towards the T3SSs in Yersinia pseudotuberculosis and Pseudomonas aeruginosa in cell-based infection models. In addition (-)-hopeaphenol reduced cell entry and subsequent intracellular growth of Chlamydia trachomatis.
Highlights
Over many years there has been an overuse of antibiotics to prevent and treat bacterial infections in humans and animals
The T3SS is an attractive drug target since it is a conserved virulence system utilized by many gram-negative animal and plant pathogens such as Yersinia spp., Pseudomonas aeruginosa, Chlamydia spp., Salmonella spp., Shigella spp, enteropathogenic Escherichia coli (EPEC) enterohemorrhagic E. coli (EHEC), and Erwinia spp. [1,7]
To establish if addition of (-)-hopeaphenol at different stages of the induction and secretion phases of Y. pseudotuberculosis T3SS affect the efficacy the compound was added at seven time points during infectious conditions
Summary
Over many years there has been an overuse of antibiotics to prevent and treat bacterial infections in humans and animals. Western blot analysis of effector proteins in total culture and supernatant, of YPIII(pIB102) wild-type bacteria incubated together with 7 different concentrations of (-)-hopeaphenol for 1 h at 26 °C followed by 3 h at 37 °C showed a clear dosedependent response for both secretion and expression of translocator protein YopD (Figure 3). Western blot analysis of the effector protein ExoS showed that the amount expressed and secreted ExoS was reduced in bacteria treated with (-)-hopeaphenol compared to the DMSO control.
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