Abstract
The type III secretion system (T3SS) consists of a syringe-like export machine injecting effectors from the bacterial cytosol directly into host cells to establish infection. This mechanism is widely distributed in gram-negative bacteria and can be targeted as an innovative strategy for the developing of anti-virulence drugs. In this study, we present an effective T3SS inhibitor, myricanol, inspired by the use of folk medicinal plants traditionally used against infections. Myricanol is a cyclic diarylheptanoid isolated from the medicinal plant Myrica nagi, which is found in South and East Asia. Bioassay-guided fractionation revealed that myricanol inhibited not only the secretion of type III effector proteins of Salmonella enterica serovar Typhimurium UK-1 χ8956 (S. Typhimurium) but also the invasion of S. Typhimurium into mammalian cells, but showed no toxicity to bacterial growth or the host cells. RNA-Seq data analysis showed that the transcription of the pathogenesis-related SPI-1 gene was significantly inhibited by myricanol. Further study demonstrated that myricanol binds physically to HilD and interferes with its DNA-binding activity to the promoters of the hilA and invF genes. In conclusion, we propose that myricanol is responsible for the anti-infectious properties of M. nagi and is a novel T3SS inhibitor of S. Typhimurium through a previously unappreciated mechanism of action.
Highlights
Antibiotic-resistant bacteria are an emerging threat to global public health and are threatening our ability to treat common infectious diseases
The concentrations of Salmonella Salmonella pathogenicity island 1 (SPI-1) effector proteins (SipA, SipB, SipC, and SipD) in the broth were significantly reduced by the treatments with myricanol (1) and monomethyl myricanol (3) at 100 μM (Figure 1B)
11acetyl substituted (2) and myricanone (5) showed significantly decreased activity compared to myricanol, which suggested that the 11-hydroxy group is essential for the T3SS inhibition
Summary
Antibiotic-resistant bacteria are an emerging threat to global public health and are threatening our ability to treat common infectious diseases. There is an urgent need for new anti-infective therapies, used alone or in combination with traditional antibiotics to prevent or treat bacterial pathogens. The Type III secretion system (T3SS) transports effector proteins into eukaryotic host cells to induce infection, which is essential for the virulence of some bacterial. Myricanol Is a T3SS Inhibitor pathogens (Galán and Wolf-Watz, 2006; Coburn et al, 2007; Nans et al, 2015; Deng et al, 2017). The T3SS-targeted therapeutic strategies disarm pathogenic bacteria but do not directly kill them directly, thereby reducing the risk of inducing resistance. T3SS appears to be a highly attractive target for the development of innovative agents against bacterial infections (Rasko and Sperandio, 2010)
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