在長期的抗生素選擇之后出現(xiàn)的對(duì)相應(yīng)抗生素產(chǎn)生耐受能力的微生物,，統(tǒng)稱耐藥菌,。所謂細(xì)菌的耐藥性，是指細(xì)菌多次與藥物接觸后，對(duì)藥物的敏感性減小甚至消失,，致使藥物對(duì)耐藥菌的療效降低甚至無效,。耐藥菌的出現(xiàn)增加了感染性疾病治愈的難度，并迫使人類尋找新的對(duì)抗微生物感染的方法,。
金黃色葡萄球菌是傷口感染的最常見細(xì)菌,，自1940年以來金黃色葡萄球菌感染已經(jīng)是世界各地醫(yī)院頭疼的問題之一，金黃色葡萄球菌是已知的抗藥性最多的細(xì)菌,。
近來,，丹麥哥本哈根大學(xué)的科學(xué)家在J Antimicrob Chemother上發(fā)表文章稱：他們?cè)谥抢麩釒в炅种参镏邪l(fā)現(xiàn)了一種天然物質(zhì)，該物質(zhì)能有效加強(qiáng)傳統(tǒng)抗生素治療的效果,。
哥本哈根大學(xué)Jes-Gitz-Holler博士在智利鱷梨植物中發(fā)現(xiàn)了一種天然化合物,，該物質(zhì)對(duì)出現(xiàn)耐藥性的金黃色葡萄球菌有抑制作用，與傳統(tǒng)的抗生素聯(lián)合運(yùn)用的話能起到協(xié)同增效的功能,。
耐藥性細(xì)菌細(xì)胞膜上通常存在一高效泵,，一旦外抗生素進(jìn)入細(xì)菌后，泵能及時(shí)向外排出抗生素,。而新發(fā)現(xiàn)的天然物質(zhì)恰巧可以抑制細(xì)菌泵的功能,，抑制抗生素向外排出，使細(xì)菌的耐藥防御機(jī)制受到破壞,。
目前,，市場上并沒有類似的抑制抗生素外排的藥品，所以新發(fā)現(xiàn)的化合物很有可能成為治療金黃色葡萄球菌感染的有效藥物,。但出于保護(hù)熱帶雨林植物,，Jes-Gitz-Holler博士強(qiáng)調(diào)我們必須要能夠在實(shí)驗(yàn)室里合成這一化學(xué)物質(zhì)。（生物谷Bioon.com）
doi:10.1093/jac/dks005
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Novel inhibitory activity of the Staphylococcus aureus NorA efflux pump by a kaempferol rhamnoside isolated from Persea lingue Nees
Jes Gitz Holler1,*,S. Brgger Christensen1,Hans-Christian Slotved2,Hasse B. Rasmussen1,Alfonso Gúzman1,Carl-Erik Olsen3,Bent Petersen4 and Per Mlgaard1
Objectives To isolate a plant-derived compound with efflux inhibitory activity towards the NorA transporter of Staphylococcus aureus.
Methods Bioassay-guided isolation was used, with inhibition of ethidium bromide efflux via NorA as a guide. Characterization of activity was carried out using MIC determination and potentiation studies of a fluoroquinolone antibiotic in combination with the isolated compound. Everted membrane vesicles of Escherichia coli cells enriched with NorA were prepared to study efflux inhibitory activity in an isolated manner.
Results The ethanolic extract of Persea lingue was subjected to bioassay-guided fractionation and led to the isolation of the known compound kaempferol-3-O-α-l-(2,4-bis-E-p-coumaroyl)rhamnoside (compound 1). Evaluation of the dose–response relationship of compound 1 showed that ethidium bromide efflux was inhibited, with an IC50 value of 2 μM. The positive control, reserpine, was found to have an IC50 value of 9 μM. Compound 1 also inhibited NorA in enriched everted membrane vesicles of E. coli. Potentiation studies revealed that compound 1 at 1.56 mg/L synergistically increased the antimicrobial activity of ciprofloxacin 8-fold against a NorA overexpresser, and the synergistic activity was exerted at a fourth of the concentration necessary for reserpine. Compound 1 was not found to exert a synergistic effect on ciprofloxacin against a norA deletion mutant. The 2,3-coumaroyl isomer of compound 1 has been shown previously not to cause acute toxicity in mice at 20 mg/kg/day.
Conclusions Our results show that compound 1 acts through inhibition of the NorA efflux pump. Combination of compound 1 with subinhibitory concentrations of ciprofloxacin renders a wild-type more susceptible and a NorA overexpresser S. aureus susceptible.
