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Vibrio vulnificus is a model pathogen for studying many other foodborne pathogens
because it causes life-threatening septicemia and gastroenteritis with a case-fatality rate exceeding 50%. Typically, the bacterial infections are treated with antibiotics that kill bacteria by impeding DNA replication, RNA synthesis, protein production, peptidoglycan biosynthesis, or tetrahydrofolate synthesis. Existing methods usually reinforce the antibiotic resistance because they inherently select for bacteria that are able to resist the drug. Therefore, I focused on the virulence factors based on the molecular Koch’s postulates. Targeting the regulation of virulence factors provides the attractive possibility that is quite different from conventional approaches.
The LuxR homologue SmcR in V. vulnificus has been recognized as an important global regulator. Although smcR is not critical for the infection of the mouse model because virulence factors are not directly regulated by SmcR, it may also be viewed as a virulence gene in that it plays a role in processes important for pathogenesis and the spread of disease. The present study established that the process mediated by SmcR is the dispersal from biofilms, which is an important event in the infectious cycle. The role of such biofilms in the epidemiology of V.
vulnificus is unclear, but presumably these cells can reconvert to active bacteria and cause subsequent outbreaks of disease. These events mediated by SmcR are
155
proposed to allow V. vulnificus to leave the host, re-enter the environment, and initiate a new cycle of infection. Interestingly, unlike other pathogens (most notably,
Pseudomonas aeruginosa) which cause chronic infections, biofilms of V. vulnificus
which causes acute infections are dispersed at a high cell density. This contrasting use of quorum sensing to control biofilms may enable these different pathogens to adapt to promote the type of disease particular to each microbe.
In addition to this function, SmcR is proposed to sense the place where their cell densities reach higher than critical levels. I speculate that during the initial stage of infection, smcR expression is repressed and expression of flhF is allowed, leading to flagella synthesis. The flagella prime V. vulnificus for initial colonization of host intestinal tissue, which is an important step required for the onset of its infectious cycle. In contrast, upon establishing preferred colonization niches with the increase in population density, the necessity of motility is superfluous, even detrimental, for a successful infection of hosts by the bacteria. In fact, flagellins of many enteropathogens have been well characterized as a major inducer as well as a target of host innate immune responses. In this context, I postulate that the temporally (eg, stationary phase-specific) and spatially (eg, cell density-dependent) integrated regulation of flagella synthesis could ensure the overall success of V.
vulnificus during pathogenesis.
156
Overall, these previous results led me to confirm that quorum sensing is essential for the survival and pathogenesis of V. vulnificus. Thus, in an effort to identify a quorum sensing inhibitor, a high throughput screening of 7,040 chemicals was performed and U-262 was singled out. The cellular level as well as the activity of SmcR are affected by U-262, indicating that U-262 could be a novel drug to prevent the SmcR-mediated pathogenesis. This novel therapy which interferes only with regulatory systems and not with growth can combat food-borne pathogens without the antibiotic resistance. It will be useful to protect food from the Vibrio spp. and help to enhance a public health.
. .
157
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175
176
177 용하여 U-262 (6-(phenylsulfonyl)nicotinonitrile)라 명명한 저분자물질을 찾
을 수 있었다. U-262는 박테리아 생장 자체는 저해하지 않으면서
178
한 결과들은 U-262가 비브리오종의 생장이 아닌 quorum sensing을 특이적
으로 제어함으로써 내성균 발생률을 낮추는 새로운 패러다임의 항미생물
제재로서 사용될 수 있다는 가능성을 제시하였다. 이런 방식에 의한 비 브리오종의 효과적인 제어를 통하여 식품안전성을 향상시키고 궁극적으 로는 공중 보건에도 기여할 수 있을 것으로 기대된다.
주요어 : 패혈증 비브리오균, quorum sensing (세포 밀도 인식 신호
주요어 : 패혈증 비브리오균, quorum sensing (세포 밀도 인식 신호