(English version below)

很久很久以前，弱小的人类面对感染束手无策。彼时，抗生素们还在沉睡。

“我们要保护洁净的水源。”

“我们发明了疫苗。”

“我们发现了……抗生素。”

一九二八年，青霉素被英国微生物学家弗莱明偶然发现。这个具有β-内酰胺环的小家伙很快成了人类的宠儿。精明的人类选择用半合成的方式从菌株中获得青霉素。

“目标——转肽酶！伪装——D-Ala-D-Ala！为了挽救生命、为了世界和平，和我一起冲啊！”

“冲啊！”

青霉素们左手举着R基盾牌，右手挥舞着羧酸佩剑，一张张小脸上带着愤怒的表情，朝着革兰氏阳性菌发起冲锋。

“有了青霉素的帮助，我们就可以高枕无忧了吧？”一些人想，看着被救治的伤兵，露出了欣慰的笑。

只是，好景不长。看似呆笨、实则狡猾的细菌们很快就有了应对之策。

“看到那个可恶的四元环了吗？就是它干掉了我们这么多弟兄！我们只要派出β-内酰胺酶小分队，深入敌后，水解切开酰胺键，便能一击毙命……”

这条讯息在细菌之间口口相传。

不久，人类沮丧地发现，向来战无不克的青霉素，似乎遇到了强敌。

细菌产生了抗药性。

“如何才能对付细菌的抗药性呢？”人类苦苦思索着这个问题。

“换用其他抗生素部队吧！他们拥有不同的作战方式。”有人提议。

“改进现有的青霉素武装，让他们也能对付β-内酰胺酶！”有人对青霉素不离不弃。

“……不如让两个部队联合作战？”

β-内酰胺酶抑制剂加入作战部队，担任在前线厮杀的青霉素的副官，为他们保驾护航。每当细菌的β-内酰胺酶小分队要偷袭青霉素时，警觉的抑制剂们都会及时跳出，和偷袭者们至死方休。

抑制剂副官们的“自杀式袭击”着实让细菌们胆战心惊，他们也因此老实了好一阵子。但抗生素大军与细菌之间的对抗就此结束了吗？

答案是否定的。

“报告！磺胺类部队请求加入战斗！”他们可以阻断细菌的叶酸合成路径。

“报告！氨基糖苷类部队请求加入战斗！”他们可以干扰细菌蛋白质的合成，但会对战场造成不同程度的损伤。

“报告！四环素类部队请求加入战斗！”他们可以阻碍细菌tRNA与核糖体的结合。

……

在经历了短暂的繁荣期后，新型武器的研制变得越发困难。与之相对的，是抗生素部队越发频繁的作战。懒惰的人类开始盲目信任、滥用抗生素。

“我们只能对付细菌，并不能对付病毒呀！”

“没有足够的作战人数，我们怎么能完全消灭敌人？”

“这点小病根本用不着派我去好嘛！”

渐渐的，抗生素们的作战方法被越来越多的细菌熟知。

“看来我马上就可以退伍了。”初代青霉素伤感地说。他原先纵横沙场、威风凛凛的招式现在已经被敌人烂熟于心。也因此，在其他伙伴被派往前线时，他只能待在后方眼巴巴地看着，磨着可能再也用不上的佩剑。他马上就可以回家种地了，可这并不是他想要的。

“我现在也开始和别人联合作战了，”四代万古霉素不无担忧，“我们有多久没有迎来新伙伴了？三年？四年？”

众抗生素默默无言。

然而，人类与疾病的对抗从未停止，仍在继续。

20200624

English Version:

The History of Antibiotic’s Fight

A long long time ago, weak humans were helpless facing infection. At that time, the antibiotics were still asleep.

“We should protect clean water.”

“We invented the vaccine.”

“We found… antibiotics.”

In 1928, penicillin was accidentally discovered by British microbiologist Fleming. A few years later, this little guy with a β-lactam ring became the darling of humans. Smart humans chose to obtain penicillin from the strain in a semi-synthetic manner.

“Target—transpeptidase! Imitation—D-Ala-D-Ala! For the love of peace, come with me!”

“Go!”

The penicillins held the R-based shield in their left hand, and waved the carboxylic acid saber in their right hand. They charged with gram-positive bacteria with angry expressions on their small faces.

“With the help of penicillin, we can sit back and relax, right?” Some people thought, looking at the wounded soldiers being treated with a gratified smile.

But nothing good lasts FOREVER. The seemingly dumb, but cunning bacteria found a countermeasure soon.

“Did you see that nasty four-membered ring? It is the murder who have killed so many of our brothers! We only need to send a team of β-lactamases, go behind the enemy lines, hydrolyze to cut the amide bond. Believe me, it must be a death blow!”

This message spread among bacteria rapidly.

Soon, human beings found with frustration that penicillin, who had always been invincible, seemed to have encountered a powerful enemy.

The bacteria developed resistance.

“How can we deal with bacterial resistance?” Humans had a bee in their heads.

“Change another antibiotic troop! They have different way to fight.” Someone suggested.

“Improve the existing penicillin arm, so that they can also deal with β-lactamase!” Some people insisted on penicillin.

“…How about letting the two units fight together?”

Beta-lactamase inhibitors joined the combat troops and acted as penicillin’s adjutants to protect them, who were fighting on the front line. Whenever the bacterial β-lactamase squad wanted to attack penicillin, the vigilant inhibitors would jump out in time, fight with the attackers until one of them died.

The “suicide attacks” of the inhibitor adjutants really scared the bacteria, and they stayed truly for a while. But was the battle between the army of antibiotics and bacteria over?

The answer was NO.

“Report! Sulfonamide troops request to join the battle!” They can block the bacteria’s folic acid synthesis pathway.

“Report! Aminoglycoside troops request to join the battle!” They can interfere with the synthesis of bacterial proteins, but would cause varying degrees of damage to the battlefield, which was undisirable.

“Report! Tetracycline troops request to join the battle!” They can prevent the binding of bacterial tRNA to ribosomes.

…

After a short period of prosperity, the development of new weapons has become increasingly difficult. In contrast, antibiotic troops were fighting more frequently. Lazy humans began to trust blindly and abuse antibiotics.

“We can only deal with bacteria, not viruses!”

“How can we completely eliminate the enemy without enough combat personnel?”

“You don’t need to send me for this minor illness!”

Gradually, more and more bacteria were familiar with the combat methods of antibiotics.

“It seems that I can retire soon.” The first-generation penicillin said sadly. His original sweeping and majestic moves on the battlefield were familiar to the enemy. Because of this, when other partners were sent to the front, he could only stay behind and watch eagerly, grinding the sword that might not be used anymore. He could go home to farm soon, but this was not what he wanted.

“I’m also starting to fight with others now,” the fourth-generation vancomycin were worried. “How long have we not welcomed new partners? Three years? Four years?”

The antibiotics were silent.

However, the confrontation between humans and diseases has never stopped and continues.