A team of Princeton researchers reported today in the journal Cell that they have found a compound, SCH-79797, that can simultaneously puncture bacterial walls and destroy folate within their cells -- while being immune to antibiotic resistance.
普林斯頓大學的一個研究小組今天在《細胞》雜誌上報告說，他們發現了一種化合物，SCH -79797，可以同時穿透細菌壁，破壞細胞內的葉酸，同時避免抗生素耐藥性。
Bacterial infections come in two flavors -- Gram-positive and Gram-negative -- named for the scientist who discovered how to distinguish them. The key difference is that Gram-negative bacteria are armored with an outer layer that shrugs off most antibiotics. In fact, no new classes of Gram-negative-killing drugs have come to market in nearly 30 years.
導致感染的細菌有兩大類別：革蘭氏陽性菌和革蘭氏陰性菌。這是以發現如何區分它們的科學家的名字命名的。關鍵的區別在於，革蘭氏陰性細菌有一層保護層，這種結構使得它可以抵抗大多數抗生素。事實上，在近30年的時間裡，沒有任何一種新的抗革蘭氏陰性菌的藥物成功地進入市場。
"This is the first antibiotic that can target Gram-positives and Gram-negatives without resistance," said Zemer Gitai, Princeton's Edwin Grant Conklin Professor of Biology and the senior author on the paper. "From a 'Why it's useful' perspective, that's the crux. But what we're most excited about as scientists is something we've discovered about how this antibiotic works -- attacking via two different mechanisms within one molecule -- that we are hoping is generalizable, leading to better antibiotics -- and new types of antibiotics -- in the future."
"這是第一個可以同時抗革蘭氏陽性菌和革蘭氏陰性菌而不產生耐藥性的抗生素，"普林斯頓大學Edwin Grant Conklin 生物學教授、該論文的資深作者Zemer Gitai說。"人們最關注的角度是'為什麼有用'。但作為科學家，我們最興奮的是發現了這種抗生素的工作原理--一個分子通過兩種不同的機制對細菌進行攻擊--我們希望這種發現是可以推廣的，從而在未來產生更好的抗生素，以及新的抗生素類別。"
The greatest weakness of antibiotics is that bacteria evolve quickly to resist them, but the Princeton team found that even with extraordinary effort, they were unable to generate any resistance to this compound. "This is really promising, which is why we call the compound's derivatives 'Irresistin,'" Gitai said.
抗生素最大的弱點，是細菌能迅速進化而產生抗藥性，但普林斯頓大學的研究小組發現，即使窮極各種手段，也沒有找到細菌們能對這種新的化合物產生抗性的跡象。「這真的很有希望，這就是為什麼我們稱這種化合物的衍生物為『不可抗素』」，Gitai說。
It's the holy grail of antibiotics research: an antibiotic that is effective against diseases and immune to resistance while being safe in humans (unlike rubbing alcohol or bleach, which are irresistibly fatal to human cells and bacterial cells alike).
這是抗生素研究的聖杯：一種對疾病有效、不產生細菌耐藥，同時對人體安全的抗生素（不像消毒酒精或漂白劑，對人體細胞和細菌細胞都有不可抗拒的致命性）。
For an antibiotics researcher, this is like discovering the formula to convert lead to gold, or riding a unicorn -- something everyone wants but no one really believes exists, said James Martin, a 2019 Ph.D. graduate who spent most of his graduate career working on this compound. "My first challenge was convincing the lab that it was true," he said.
對於抗生素研究人員來說，這就像發現了將鉛轉化為黃金的公式，或者騎上了獨角獸—這是人人都想得到的東西，但沒有人真正相信它的存在，2019年博士畢業生James Martin說（譯者註：獨角獸是一種西方神話動物，人們相信他的獨角能變毒水為飲用水並包治百病）。他的大部分研究生生涯都在研究這種化合物。"我的第一個挑戰是讓我實驗室裡的同事們相信這是真的，"他說。
But irresistibility is a double-edged sword. Typical antibiotics research involves finding a molecule that can kill bacteria, breeding multiple generations until the bacteria evolve resistance to it, looking at how exactly that resistance operates, and using that to reverse-engineer how the molecule works in the first place.
但不可抗性是一把雙刃劍。典型的抗生素研究通常在遵循這個思路，即找到一個可以殺死細菌的分子，然後將細菌暴露在這個抗菌分子的作用之下，連續培育多代，直到細菌進化出耐藥性，研究這種耐藥性究竟是如何運作的，並以此來逆向推測分子當初是怎麼殺死細菌的。
But since SCH-79797 is irresistible, the researchers had nothing to reverse engineer from.
但由於SCH-79797無法讓細菌產生抗藥性，研究人員沒有切入點用以逆向研究其工作機理。
"This was a real technical feat," said Gitai. "No resistance is a plus from the usage side, but a challenge from the scientific side."
"這是一個真正的技術壯舉，"Gitai說。"不產生耐藥性，從使用方面來說是個加分項，但從科研方面來說是個難題。"
The research team had two huge technical challenges: Trying to prove the negative -- that nothing can resist SCH-79797 -- and then figuring out how the compound works.
研究小組面臨兩個巨大的技術挑戰。一是提供一個反證，即沒有任何東西可以抵抗SCH-79797，二是弄清楚這種化合物是如何工作的。
To prove its resistance to resistance, Martin tried endless different assays and methods, none of which revealed a particle of resistance to the SCH compound. Finally, he tried brute force: for 25 days, he "serially passaged" it, meaning that he exposed bacteria to the drug over and over and over again. Since bacteria take about 20 minutes per generation, the germs had millions of chances to evolve resistance -- but they didn't. To check their methods, the team also serially passaged other antibiotics (novobiocin, trimethoprim, nisin and gentamicin) and quickly bred resistance to them.
為了證明藥物不產生抗藥性，Martin嘗試了無數種不同的檢測工具和方法，但都沒有發現SCH化合物的一絲耐藥性。最後，他用了蠻力：在25天裡，他對它進行了 "耐藥接力"，也就是說，他一次又一次地將細菌暴露在藥物中。由於細菌每繁殖一代大約需要20分鐘，細菌有數百萬次機會進化出耐藥性--然後耐藥菌株最終並沒有出現。為了檢查他們的方法，該團隊還對其他抗生素（新黴素、甲氧苄啶、乳酸鏈球菌素和慶大黴素）進行了同樣的過程，並迅速培育出對它們的抗藥性。
Proving a negative is technically impossible, so the researchers use phrases like "undetectably-low resistance frequencies" and "no detectable resistance," but the upshot is that SCH-79797 is irresistible -- hence the name they gave to its derivative compounds, Irresistin.
證明負面斷言在技術上是不可能的，所以研究人員使用了 "無法檢測-低耐藥頻率 "和 "無法檢測到耐藥性 "這樣的修飾語，但最終所有的試驗結果都證實，SCH-79797是抗耐藥的--因此他們給它的衍生化合物起了個名字，叫「不可抗素」。
They also tried using it against bacterial species that are known for their antibiotic resistance, including Neisseria gonorrhoeae, which is on the top 5 list of urgent threats published by the Center for Disease Control and Prevention.
他們還嘗試用它來對付那些以抗生素耐藥性著稱的細菌菌株，包括淋球奈瑟氏菌，它是疾病預防控制中心公布的5大緊急威脅名單中的一員。
"Gonorrhea poses a huge problem with respect to multidrug resistance," said Gitai. "We've run out of drugs for gonorrhea. With most common infections, the old-school generic drugs still work. When I got strep throat two years ago, I was given penicillin-G -- the penicillin discovered in 1928! But for N. gonorrhoeae, the standard strains that are circulating on college campuses are super drug resistant. What used to be the last line of defense, the break-glass-in-case-of-emergency drug for Neisseria, is now the front-line standard of care, and there really is no break-glass backup anymore. That's why this one is a particularly important and exciting one that we could cure."
「淋球奈瑟氏菌在多藥耐藥性方面是一個巨大的問題，」Gitai說。「我們治療淋病的藥物已經用完了。對於大多數常見的感染，傳統的非專利藥仍然有效。兩年前我得了鏈球菌性咽喉炎，醫生給我注射了青黴素g——1928年發現的青黴素! 但是對於淋球奈瑟氏菌，在大學校園中流行的菌株是超級耐藥的。曾經是治療奈瑟氏菌最後一道防線的應急藥物，現在進了一線的標準治療方案，而且真的再也沒有其他應急藥物可用了。這就是為什麼對於治癒淋病來說，這是一個特別重要和令人興奮的福音。」
The researchers even got a sample of the most resistant strain of N. gonorrhoeae from the vaults of the World Health Organization -- a strain that is resistant to every known antibiotic -- and "Joe showed that our guy still killed this strain," Gitai said, referring to Joseph Sheehan, a co-first-author on the paper and the lab manager for the Gitai Lab. "We're pretty excited about that."
研究人員甚至從世界衛生組織的菌種庫中得到了最耐藥的淋球奈瑟氏菌株的樣本，這種菌株對所有已知的抗生素都有抗藥性。"Joe的實驗表明，我們的藥仍然殺死了這種菌株，"Gitai說，他指的是該論文的共同第一作者、Gitai實驗室的實驗室經理Joseph Sheehan。"我們對此相當興奮。"