*仅供医学专业人士阅读参考
没想到有一天，抗生素竟然遭到了非抗生素的“背刺”。
近期，马萨诸塞大学医学院Amir Mitchell团队发表了一项重要研究成果，他们在分析了186种抗生素和非抗生素药物后发现，非抗生素与抗生素之间很多时候呈正交关系，即它们通过不同的机制作用于细菌。
值得注意的是，药物输送相关基因的分析显示，虽然非抗生素与抗生素对细菌的作用机制不同，但他们却都受到了细菌外排（细菌耐药的一个重要机制）的影响。这也就意味着，细菌在对非抗生素产生耐药性的同时，也会不小心引发抗生素交叉耐药。
研究发表在顶级期刊《科学》上。
论文首页截图
抗生素耐药是全球健康的最大问题之一，据估计，到2050年，每年将会有1000万人死于耐药性感染。更让人头疼的是，从1990年以来，人类发现新的抗生素种类相当有限。而近年来，非抗生素展现出的抗菌活性让人们看到了新的希望。
然而更大的问题是，我们对非抗生素的抗菌活性还存在很多未知，比如非抗生素是如何作用于细菌的，是否和抗生素一样？它是否会导致细菌耐药？等等，总之这些问题都有待解答。
Amir Mitchell团队为了搞清楚非抗生素作用于细菌的机制，他们选取了1280种药物，这些药物包括市面上已经获批了的，还有一些是正在研发中的药物，其中226种为抗生素，1054种为非抗生素。
通过观察每个药物对大肠杆菌的影响，研究人员最终选取了186种可以显著抑制大肠杆菌生长的药物（103种抗生素和83种非抗生素）。
药物筛选
接下来，研究人员想知道，非抗生素的抑菌作用是否可以归咎于与抗生素有着一致的化学相似性。
通过计算Tanimoto系数（0.8以上就是高度相似了），研究人员发现，同类抗生素，即对细菌有着相同作用机制的抗生素们通常具有很高的化学相似性，但不同类型的抗生素、抗生素和非抗生素，以及非抗生素之间化学相似性较低。
这一发现表明，非抗生素显示出的抗菌活性，并不能归咎于它们在化学特征上类似于抗生素，而更可能是它们通过不同的机制来抑制细菌生长。
随后，研究人员利用混合基因筛选方法捕获了90种抗生素对细菌的作用机制，并生成了针对抗生素的药物相关性网络。
在将非抗生素加入到抗生素的药物相关性网络中后，研究人员发现，非抗生素与抗生素之间呈正交关系，也就是说，大多数非抗生素与抗生素作用机制的确不同（如果存在一样的机制，网络模块会聚集在一起）。
药物相关性网络
不过意外的是，一些非抗生素之间却存在相关性。于是研究人员又构建了非抗生素的药物相关性网络，结果共发现九个独立的网络模块，共涉及如生物合成和代谢过程，脂多糖生物合成相关的过程等多种生物功能。
接下来，研究人员观察了一些参与细菌膜通透性和转运的基因对药物抗菌活性的影响，结果发现删除细菌的某些基因会增加药物的敏感性（尤其是一些编码抗性-结瘤-分裂家族转运蛋白、Tol-Pal系统和外膜蛋白的基因）。
敲除编码膜通透性和转运的基因，会增加抗生素和非抗生素的抗菌活性
此外，研究还发现，有26种包括抗生素和非抗生素在内药物都会受到五种或更多不同转运系统的影响。根据以上结果，研究人员推测，尽管大多数非抗生素与抗生素作用机制不同，但若因为非抗生素相关膜通透性和转运途径导致的耐药，那么细菌也可能通过同样途径对抗生素产生耐药。
为了证明这一猜想，研究人员打算做一个药物抗性演化实验。研究人员从非抗生素的药物相关性网络的不同模块中选取了链脲佐菌素（Streptozotocin）、三氯苯达唑（Triclabendazole）和舍曲林（sertraline）这三种非抗生素，并将其放置于5种独立进化的大肠杆菌中。
结果发现，对链脲佐菌素、三氯苯达唑适应的演化细菌完全耐药，而对舍曲林适应的演化细菌竟然增加了两倍以上的抗药性。通过对演化细菌进行基因组测序，研究人员发现了三种的非抗生素导致细菌耐药的机制。
对链脲佐菌素耐药的细菌进化出了让
nagE基因失活
（这一基因编码葡萄糖-6－磷酸运输体，负责把药物运输到细菌内）的本事，总结就是谁都别想进来。
对三氯苯达唑耐药的细菌让编码翻译起始因子IF2的基因突变了（非抗生素可与IF2结合可组织细菌蛋白质生成），总结就是细菌换了个锁芯，主打一个让你有钥匙也打不开。
对舍曲林耐药的细菌让调节外排泵的基因（
marR、acrR和
lon）发生了突变，增加了多种外排途径，总结就是谁来都得给撵出去。
鉴于细胞外排也是细菌对抗生素耐药的主要机制，研究人员认为对舍曲林耐药细菌也可能无意间促进了其对抗生素的耐药（围绕舍曲林耐药菌的抗生素耐药性实验也证实了这一点）。
这就好比抗生素和细菌要打架，非抗生素巴巴地冲过去给细菌送了一份装备经验大礼包，这让抗生素怎么玩，纯纯背刺。
总之，该研究通过遗传筛选和网络分析，发现一些非抗生素药物可能存在与抗生素不同的抑菌机制，这为开发新型抗菌药物提供了新的方向。不过在抗生素使用过程中导致的抗生素耐药也是一个亟须关注的问题。
参考文献：
[1]Guillen M N, Li C, Rosener B, et al. Antibacterial activity of nonantibiotics is orthogonal to standard antibiotics[J]. Science, 2024: eadk7368.
本文丨张金旭
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#000;--weui-TAG-TEXT-RED: rgba(250, 81, 81, .6);--weui-TAG-BACKGROUND-RED: rgba(250, 81, 81, .1);--weui-TAG-TEXT-ORANGE: rgba(250, 157, 59, .6);--weui-TAG-BACKGROUND-ORANGE: rgba(250, 157, 59, .1);--weui-TAG-TEXT-GREEN: rgba(6, 174, 86, .6);--weui-TAG-BACKGROUND-GREEN: rgba(6, 174, 86, .1);--weui-TAG-TEXT-BLUE: rgba(16, 174, 255, .6);--weui-TAG-BACKGROUND-BLUE: rgba(16, 174, 255, .1);--weui-TAG-TEXT-BLACK: rgba(255, 255, 255, .5);--weui-TAG-BACKGROUND-BLACK: rgba(255, 255, 255, .05)}}@media screen and (min-width:1024px){body:not(.pages_skin_pc) .wx-root[data-weui-theme=dark],body:not(.pages_skin_pc) body[data-weui-theme=dark]{--appmsgExtra-BG: #121212}}@media screen and (min-width:1024px){body:not(.pages_skin_pc)body:not(.pages_skin_pc){background:var(--weui-BG-2)}}@media screen and (min-width:1024px) and (prefers-color-scheme:dark){body:not(.pages_skin_pc) .wx-root[data-weui-mode=care]:not([data-weui-theme=light]),body:not(.pages_skin_pc) body[data-weui-mode=care]:not([data-weui-theme=light]){--weui-BG-0: #111;--weui-BG-1: #1e1e1e;--weui-BG-2: #191919;--weui-BG-3: #202020;--weui-BG-4: #404040;--weui-BG-5: #2c2c2c;--weui-FG-0: rgba(255, 255, 255, .85);--weui-FG-HALF: rgba(255, 255, 255, .65);--weui-FG-1: rgba(255, 255, 255, .55);--weui-FG-2: rgba(255, 255, 255, .35);--weui-FG-3: rgba(255, 255, 255, .1);--weui-FG-4: rgba(255, 255, 255, .15);--weui-FG-5: rgba(255, 255, 255, .1);--weui-RED: #fa5151;--weui-ORANGERED: #ff6146;--weui-ORANGE: #c87d2f;--weui-YELLOW: #cc9c00;--weui-GREEN: #74a800;--weui-LIGHTGREEN: #3eb575;--weui-BRAND: #07c160;--weui-BLUE: #10aeff;--weui-INDIGO: #1196ff;--weui-PURPLE: #8183ff;--weui-WHITE: rgba(255, 255, 255, .8);--weui-LINK: #7d90a9;--weui-TEXTGREEN: #259c5c;--weui-FG: #fff;--weui-BG: #000;--weui-TAG-TEXT-RED: rgba(250, 81, 81, .6);--weui-TAG-BACKGROUND-RED: rgba(250, 81, 81, .1);--weui-TAG-TEXT-ORANGE: rgba(250, 157, 59, .6);--weui-TAG-BACKGROUND-ORANGE: rgba(250, 157, 59, .1);--weui-TAG-TEXT-GREEN: rgba(6, 174, 86, .6);--weui-TAG-BACKGROUND-GREEN: rgba(6, 174, 86, .1);--weui-TAG-TEXT-BLUE: rgba(16, 174, 255, .6);--weui-TAG-BACKGROUND-BLUE: rgba(16, 174, 255, .1);--weui-TAG-TEXT-BLACK: rgba(255, 255, 255, .5);--weui-TAG-BACKGROUND-BLACK: rgba(255, 255, 255, .05)}}@media screen and (min-width:1024px) and (prefers-color-scheme:dark){body:not(.pages_skin_pc) .wx-root:not([data-weui-theme=light]),body:not(.pages_skin_pc) body:not([data-weui-theme=light]){--weui-BG-0: #111;--weui-BG-1: #1e1e1e;--weui-BG-2: #191919;--weui-BG-3: #202020;--weui-BG-4: #404040;--weui-BG-5: #2c2c2c;--weui-FG-0: rgba(255, 255, 255, .8);--weui-FG-HALF: rgba(255, 255, 255, .6);--weui-FG-1: rgba(255, 255, 255, .5);--weui-FG-2: rgba(255, 255, 255, .3);--weui-FG-3: rgba(255, 255, 255, .1);--weui-FG-4: rgba(255, 255, 255, .15);--weui-FG-5: rgba(255, 255, 255, .1);--weui-RED: #fa5151;--weui-ORANGERED: #ff6146;--weui-ORANGE: #c87d2f;--weui-YELLOW: #cc9c00;--weui-GREEN: #74a800;--weui-LIGHTGREEN: #3eb575;--weui-BRAND: #07c160;--weui-BLUE: #10aeff;--weui-INDIGO: #1196ff;--weui-PURPLE: #8183ff;--weui-WHITE: rgba(255, 255, 255, .8);--weui-LINK: #7d90a9;--weui-TEXTGREEN: #259c5c;--weui-FG: #fff;--weui-BG: #000;--weui-TAG-TEXT-RED: rgba(250, 81, 81, .6);--weui-TAG-BACKGROUND-RED: rgba(250, 81, 81, .1);--weui-TAG-TEXT-ORANGE: rgba(250, 157, 59, .6);--weui-TAG-BACKGROUND-ORANGE: rgba(250, 157, 59, .1);--weui-TAG-TEXT-GREEN: rgba(6, 174, 86, .6);--weui-TAG-BACKGROUND-GREEN: rgba(6, 174, 86, .1);--weui-TAG-TEXT-BLUE: rgba(16, 174, 255, .6);--weui-TAG-BACKGROUND-BLUE: rgba(16, 174, 255, .1);--weui-TAG-TEXT-BLACK: rgba(255, 255, 255, .5);--weui-TAG-BACKGROUND-BLACK: rgba(255, 255, 255, .05)}}@media screen and (min-width:1024px) and (prefers-color-scheme:dark){body:not(.pages_skin_pc) .wx-root:not([data-weui-theme=light]),body:not(.pages_skin_pc) body:not([data-weui-theme=light]){--appmsgExtra-BG: 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#06ae56;--weui-FG: #000;--weui-BG: #fff;--weui-TAG-TEXT-RED: rgba(250, 81, 81, .6);--weui-TAG-BACKGROUND-RED: rgba(250, 81, 81, .1);--weui-TAG-TEXT-ORANGE: #fa9d3b;--weui-TAG-BACKGROUND-ORANGE: rgba(250, 157, 59, .1);--weui-TAG-TEXT-GREEN: #06ae56;--weui-TAG-BACKGROUND-GREEN: rgba(6, 174, 86, .1);--weui-TAG-TEXT-BLUE: #10aeff;--weui-TAG-BACKGROUND-BLUE: rgba(16, 174, 255, .1);--weui-TAG-TEXT-BLACK: rgba(0, 0, 0, .5);--weui-TAG-BACKGROUND-BLACK: rgba(0, 0, 0, .05)}.wx-root,body{--weui-BTN-ACTIVE-MASK: rgba(0, 0, 0, .1)}.wx-root,body{--weui-BTN-DEFAULT-ACTIVE-BG: #e6e6e6}.wx-root,body{--weui-DIALOG-LINE-COLOR: rgba(0, 0, 0, .1)}.wx-root,body{--weui-BG-COLOR-ACTIVE: #ececec}@media(prefers-color-scheme:dark){.wx-root:not([data-weui-theme=light]),body:not([data-weui-theme=light]){--weui-BTN-ACTIVE-MASK: rgba(255, 255, 255, .1)}}@media(prefers-color-scheme:dark){.wx-root:not([data-weui-theme=light]),body:not([data-weui-theme=light]){--weui-BTN-DEFAULT-ACTIVE-BG: rgba(255, 255, 255, .126)}}@media(prefers-color-scheme:dark){.wx-root:not([data-weui-theme=light]),body:not([data-weui-theme=light]){--weui-DIALOG-LINE-COLOR: rgba(255, 255, 255, .1)}}@media(prefers-color-scheme:dark){.wx-root:not([data-weui-theme=light]),body:not([data-weui-theme=light]){--APPMSGCARD-BG: #1E1E1E}}@media(prefers-color-scheme:dark){.wx-root:not([data-weui-theme=light]),body:not([data-weui-theme=light]){--APPMSGCARD-LINE-BG: rgba(255, 255, 255, .07)}}@media(prefers-color-scheme:dark){.wx-root:not([data-weui-theme=light]),body:not([data-weui-theme=light]){--weui-BG-COLOR-ACTIVE: #373737}}@media(prefers-color-scheme:dark){.wx-root:not([data-weui-theme=light]),body:not([data-weui-theme=light]){--weui-BG-6: rgba(255, 255, 255, .1);--weui-ACTIVE-MASK: rgba(255, 255, 255, .1)}}@media(prefers-color-scheme:dark){.wx-root:not([data-weui-theme=light]),body:not([data-weui-theme=light]){--weui-REDORANGE: #ff6146;--weui-BG-0: #111;--weui-BG-1: #1e1e1e;--weui-BG-2: #191919;--weui-BG-3: #202020;--weui-BG-4: #404040;--weui-BG-5: #2c2c2c;--weui-FG-0: rgba(255, 255, 255, .8);--weui-FG-HALF: rgba(255, 255, 255, .6);--weui-FG-1: rgba(255, 255, 255, .5);--weui-FG-2: rgba(255, 255, 255, .3);--weui-FG-3: rgba(255, 255, 255, .1);--weui-FG-4: rgba(255, 255, 255, .15);--weui-FG-5: rgba(255, 255, 255, .1);--weui-RED: #fa5151;--weui-ORANGERED: #ff6146;--weui-ORANGE: #c87d2f;--weui-YELLOW: #cc9c00;--weui-GREEN: #74a800;--weui-LIGHTGREEN: #3eb575;--weui-BRAND: #07c160;--weui-BLUE: #10aeff;--weui-INDIGO: #1196ff;--weui-PURPLE: #8183ff;--weui-WHITE: rgba(255, 255, 255, .8);--weui-LINK: #7d90a9;--weui-TEXTGREEN: #259c5c;--weui-FG: #fff;--weui-BG: #000;--weui-TAG-TEXT-RED: rgba(250, 81, 81, .6);--weui-TAG-BACKGROUND-RED: rgba(250, 81, 81, .1);--weui-TAG-TEXT-ORANGE: rgba(250, 157, 59, .6);--weui-TAG-BACKGROUND-ORANGE: rgba(250, 157, 59, .1);--weui-TAG-TEXT-GREEN: rgba(6, 174, 86, .6);--weui-TAG-BACKGROUND-GREEN: rgba(6, 174, 86, .1);--weui-TAG-TEXT-BLUE: rgba(16, 174, 255, .6);--weui-TAG-BACKGROUND-BLUE: rgba(16, 174, 255, .1);--weui-TAG-TEXT-BLACK: rgba(255, 255, 255, .5);--weui-TAG-BACKGROUND-BLACK: rgba(255, 255, 255, .05)}}@media(prefers-color-scheme:dark){.wx-root:not([data-weui-theme=light]),body:not([data-weui-theme=light]){--discussInput-BG: rgba(255, 255, 255, .03)}}@media(prefers-color-scheme:dark){.wx-root:not([data-weui-theme=light]),body:not([data-weui-theme=light]){--nickName-FG: #959595}}@media(prefers-color-scheme:dark){.wx-root:not([data-weui-theme=light]),body:not([data-weui-theme=light]){--weui-BG-0: #111;--weui-BG-1: #1e1e1e;--weui-BG-2: #191919;--weui-BG-3: #202020;--weui-BG-4: #404040;--weui-BG-5: #2c2c2c;--weui-FG-0: rgba(255, 255, 255, .8);--weui-FG-HALF: rgba(255, 255, 255, .6);--weui-FG-1: rgba(255, 255, 255, .5);--weui-FG-2: rgba(255, 255, 255, .3);--weui-FG-3: rgba(255, 255, 255, .1);--weui-FG-4: rgba(255, 255, 255, .15);--weui-FG-5: rgba(255, 255, 255, .1);--weui-RED: #fa5151;--weui-ORANGERED: #ff6146;--weui-ORANGE: #c87d2f;--weui-YELLOW: #cc9c00;--weui-GREEN: #74a800;--weui-LIGHTGREEN: #3eb575;--weui-BRAND: #07c160;--weui-BLUE: #10aeff;--weui-INDIGO: #1196ff;--weui-PURPLE: #8183ff;--weui-WHITE: rgba(255, 255, 255, .8);--weui-LINK: #7d90a9;--weui-TEXTGREEN: #259c5c;--weui-FG: #fff;--weui-BG: #000;--weui-TAG-TEXT-RED: rgba(250, 81, 81, .6);--weui-TAG-BACKGROUND-RED: rgba(250, 81, 81, .1);--weui-TAG-TEXT-ORANGE: rgba(250, 157, 59, .6);--weui-TAG-BACKGROUND-ORANGE: rgba(250, 157, 59, .1);--weui-TAG-TEXT-GREEN: rgba(6, 174, 86, .6);--weui-TAG-BACKGROUND-GREEN: rgba(6, 174, 86, .1);--weui-TAG-TEXT-BLUE: rgba(16, 174, 255, .6);--weui-TAG-BACKGROUND-BLUE: rgba(16, 174, 255, .1);--weui-TAG-TEXT-BLACK: rgba(255, 255, 255, .5);--weui-TAG-BACKGROUND-BLACK: rgba(255, 255, 255, .05)}}@media(prefers-color-scheme:dark){.wx-root:not([data-weui-theme=light]),body:not([data-weui-theme=light]){--appmsgExtra-BG: #121212}}.rich_media_content p{clear:both;min-height:1em}td p{margin:0;padding:0}
div.autoTypeSetting24psection > p,div.autoTypeSetting24psection > section{margin-bottom: 24px;}
