生物谷報(bào)道：美國(guó)科學(xué)家的一項(xiàng)最新研究表明,，利用不同靶標(biāo)和路徑開發(fā)的抗生素具一個(gè)共同的殺菌機(jī)制,，它們具有相同的“終極武器”——羥基自由基分子，從而破壞細(xì)菌的DNA,、蛋白質(zhì)和脂肪,。該研究成果有助于科學(xué)家未來(lái)開發(fā)出超級(jí)藥物。相關(guān)論文發(fā)表在9月7日的《細(xì)胞》雜志上,。
為了開發(fā)新的藥物,，美國(guó)波士頓大學(xué)的James Collins帶領(lǐng)的小組對(duì)從藥物使用到細(xì)胞死亡的全過(guò)程進(jìn)行了分段研究。他們?cè)l(fā)現(xiàn)一種抗生素會(huì)影響細(xì)菌的DNA復(fù)制,，從而釋放出自由基,。在最新的研究中，利用熒光染料標(biāo)記羥基分子,，研究人員驚訝地發(fā)現(xiàn),，在另外兩種攻擊細(xì)胞壁和阻礙蛋白制造的抗生素中，與第一種情況相同的自由基仍然會(huì)出現(xiàn),。
科學(xué)家通常認(rèn)為,，這三種不同路徑的抗生素彼此差異很大,，不過(guò),，新的研究卻說(shuō)明，它們具有相同的伎倆,。不過(guò),，研究人員強(qiáng)調(diào)，這種相似性只存在于殺菌劑（包括青霉素）中,，阻礙細(xì)菌生長(zhǎng)的抑菌藥物并不會(huì)引起自由基的釋放,。
臨床上每一種抗生素都有一定的貨架期，實(shí)際上就是細(xì)菌產(chǎn)生抗性的時(shí)間問(wèn)題,。因此藥劑師需要不斷地創(chuàng)造新的抗生素,。新的研究成果有望為未來(lái)抗生素的設(shè)計(jì)開辟一條新的道路。Collins表示,，藥劑師可以通過(guò)添加特定的化學(xué)藥物,，來(lái)阻礙細(xì)菌修復(fù)DNA和抵御自由基的作用，從而加強(qiáng)環(huán)丙沙星等經(jīng)典抗生素的效力,，并將它們制成超級(jí)藥物,。
美國(guó)北卡羅萊納大學(xué)的Scott Singleton表示，這一令人興奮的發(fā)現(xiàn)可以讓許多副作用較大（因高劑量引起）的傳統(tǒng)藥物重回貨架,。如果這些藥物更加有效,，它們的用量就會(huì)降低,，副作用也會(huì)減小。
加拿大McMaster大學(xué)的生物化學(xué)家Gerry Wright說(shuō),，“這正是當(dāng)下抗生素研究領(lǐng)域所需要的發(fā)現(xiàn),，對(duì)我們自認(rèn)為‘知曉’的事實(shí)的新認(rèn)識(shí)。”（科學(xué)網(wǎng) 任霄鵬/編譯）
原始出處:
Cell, Vol 130, 797-810, 07 September 2007
Article
A Common Mechanism of Cellular Death Induced by Bactericidal Antibiotics
Michael A. Kohanski,1,2,5,6 Daniel J. Dwyer,1,3,6 Boris Hayete,1,4 Carolyn A. Lawrence,1,2 and James J. Collins1,2,3,4,
1 Center for BioDynamics and Center for Advanced Biotechnology, Boston University, Boston, MA 02215, USA
2 Department of Biomedical Engineering, Boston University, Boston, MA 02215, USA
3 Program in Molecular Biology, Cell Biology, and Biochemistry, Boston University, Boston, MA 02215, USA
4 Bioinformatics Program, Boston University, Boston, MA 02215, USA
5 Boston University School of Medicine, Boston, MA 02118, USA
Corresponding author
James J. Collins
jcollins@bu.edu
Summary
Antibiotic mode-of-action classification is based upon drug-target interaction and whether the resultant inhibition of cellular function is lethal to bacteria. Here we show that the three major classes of bactericidal antibiotics, regardless of drug-target interaction, stimulate the production of highly deleterious hydroxyl radicals in Gram-negative and Gram-positive bacteria, which ultimately contribute to cell death. We also show, in contrast, that bacteriostatic drugs do not produce hydroxyl radicals. We demonstrate that the mechanism of hydroxyl radical formation induced by bactericidal antibiotics is the end product of an oxidative damage cellular death pathway involving the tricarboxylic acid cycle, a transient depletion of NADH, destabilization of iron-sulfur clusters, and stimulation of the Fenton reaction. Our results suggest that all three major classes of bactericidal drugs can be potentiated by targeting bacterial systems that remediate hydroxyl radical damage, including proteins involved in triggering the DNA damage response, e.g., RecA.
