Pharmacodynamic Evaluation Of Turmeric Extract Against Staphylococcus Aureus Pneumonia

Staphylococcus aureus is an important zoonosis pathogen that causes a broadspectrum of diseases, ranging from soft-tissue infections to life threatening deep tissuedamage, and even more invasive diseases, such as osteomyelitis, endocarditis andpneumonia, which plays an important role in clinical infections. Dairy cow mastitiscaused by S. aureus is one of the most serious diseases in animals, resulting in aserious problem for the dairy industry. In addition to causing major economic losses,dairy cow mastitis is likely to have a negative impact on public health, which is alsothe main source of harmful bacteria in milk and dairy products. Among theseinfections, S. aureus pneumonia is considered one of the most prevalent and seriousinfections with significant morbidity and mortality. Moreover, S. aureus is also animportant foodborne pathogen, causing staphylococcal gastroenteritis and foodpoisoning in humans. Over the past few years, since the first use of antibiotics in theclinic in1960s, the emergence and development of resistance have rendered S. aureusa world challenge to the human and animal health, especially with the emergence ofmethicillin-resistant S. aureus (MRSA), accounting for more than half of allstaphylococcal pneumonia isolates. Along with the multi-drug resistance phenomenon,shortcomings associated with the limited number of currently approved treatments forMRSA infection support the need for new treatment options against staphylococcalinfections. Recently, it has been reported that some compounds can target the bacterialvirulence factors and inhibit their activity, suggesting a promising strategy for thetreatment of S. aureus-mediated diseases.S. aureus produces a wide variety of virulence factors that contribute to itspathogenesis, including exotoxin and surface-associated proteins. The virulence factorα-hemolysin (Hla) is a33.2kDa pore-forming hemolytic toxin, which is produced bymost pathogenic strains of S. aureus. It is known to cause the destruction of numerous types of mammalian cells, including erythrocytes, lymphocytes, alveolar epithelialcells, macrophages and monocytes. After secreted by S. aureus as a water-solublemonomer, Hla binds to the target cell membrane. Upon binding, seven Hla monomerscan self-assemble to form a232.4kDa membrane-inserted heptamer that penetratesthe cell membrane, which ultimately results in cell damage and death. There areincreasing evidence implicating Hla in the pathogenesis of human diseases, especiallyin staphylococcal pneumonia. S. aureus mutant strains lacking hla exhibit acorresponding decrease in virulence observed in animal models of pneumonia.Consistent with these findings, current epidemic USA300isolates of MRSA thatcause a significant disease burden in healthy hosts display both increased Hlaexpression and virulence in experimental models. Consequently, there is considerableinterest in the development of small molecule inhibitors or antibodies for thetreatment of S. aureus Hla-induced diseases.The application of traditional Chinese medicine (TCM) has a long history ofthousands of years in China, and the anti-infection effect of TCM has already beenconfirmed by researchers at home and abroad. TCM has a variety of advantages, suchas low toxicity, high safety and extensive sources. Therefore, the investigation ofinhibitory effects of TCM on the main virulence factors of S. aureus would providenew ideas for the treatment of S. aureus infection. Turmeric (Jianghuang) comes fromthe root of the plant Curcuma longa, a member of the ginger family, which has avariety of biological activities including anti-cancer, anti-inflammatory andantibacterial effects. Turmeric has been used in clinical treatment of cardiovasculardiseases, inflammatory diseases and cancer. In this thesis, we investigated the effect ofturmeric extract on the staphylococcal Hla and its protective effect against S. aureuspneumonia in a mouse model of infection. We found that the MICs of turmeric extractfor all of the S. aureus strains tested were512μg/ml, and it had no effects on thegrowth of S. aureus8325-4with the concentrations of8-64μg/ml, indicating thatturmeric extract has little anti-S. aureus activity. However, with these concentrationsof turmeric extract, the hemolytic activity in the supernant were significantly reduced,as well as the hemolytic activity of the purified Hla. We also found that turmericextract did not have acute toxicity, and it could alleviate A549cell injury caused by S. aureus. The findings in animal experiment indicated that treated mice with turmericextract significantly decreased the mortality and the lung injury was alleviated,indicating that turmeric extract can protect mice from S. aureus pneumonia.