Antibiotics Of The Future
Scientists are working to develop new strategies to combat the growing threat of germs that current antibiotics can't fight.
Some researchers are testing new substances, such as silver, to combine with antibiotics to boost their killing power. Other researchers are making use of genetic sequencing of bacteria to help develop killer drugs at a faster pace than medical science was capable of in the past.
Another strategy aims to render harmful bacteria incapable of infecting people, rather than killing the germs outright. One such technique would neutralize disease-causing toxins by disrupting the bacteria's internal mechanisms.
另一种策略意在让 有害细菌无法感染人类而不是将病菌 一举消灭。这样一种技术可以通过破坏细菌的内在机理来中和致病毒素。
Antibiotic resistance is a growing threat to public health, medical officials say. Common germs such as Escherichia coli, or E. coli, which can cause urinary tract and other infections, and Neisseria gonorrhoeae, which causes gonorrhea, are becoming harder to treat because they increasingly don't respond to antibiotics. Some two million people in the U.S. are infected each year by antibiotic-resistant bacteria and 23,000 die as a result, according to the Centers for Disease Control and Prevention. The CDC says it doesn't have historical numbers.
医疗官员说，抗生素耐药性对公共卫生构成了越来越大的威胁。像能够引起尿路及其它感染的大肠杆菌和引起淋病的淋球菌这些常见病菌都变得越发难以治疗，因为它们对抗生素的反应日渐减弱。根据美国疾病控制与预防中心(Centers for Disease Control and Prevention，简称疾控中心)的数据，美国每年有大约两百万人感染抗药性细菌，由此造成的死亡人数达23,000人。疾控中心说它没有历史数据。
One of the biggest threats is from Enterobacteriaceae, a family of germs that naturally lives in the gut and includes E. coli, the CDC says. There are about 9,000 cases a year of infections from the germs that can't be treated with usual antibiotics, resulting in 610 deaths. In 1998, there was just one case. Patients who don't respond to normal antibiotics are given older drugs that had been discontinued because of severe side effects, such as kidney damage, the CDC says.
Scientists say that Enterobacteriaceae are particularly hard to kill because of an outer cell wall that prevents many antibiotics from penetrating. James J. Collins, a professor of biomedical engineering at Boston University and Harvard University, and his colleagues recently discovered that adding trace amounts of silver -- long known to have antimicrobial properties -- allows the common antibiotic vancomycin to work against E. coli, whereas the antibiotic isn't effective against the microbe on its own. The silver appears to make the outer walls of the bacteria more permeable, allowing the antibiotic to get in and do its job, says Dr. Collins, who published the findings in the journal Science Translational Medicine in June.
科学家说肠杆菌特别难消灭，因为它的一个外层细胞壁可以阻止很多抗生素的侵入。身为波士顿大学和哈佛大学生物医学工程教授的詹姆斯·J·科林斯(James J. Collins)最近和他的同事发现加入微量的银——人们早已知道它具有抗菌的特性——可以让万古霉素这样的普通抗生素杀灭大肠杆菌，而这种抗生素仅靠自身是不能有效消灭那种细菌的。科林斯说，看来银让细菌的外层细胞壁更容易被穿透，使抗生素得以进入并发挥它的作用。他在六月的《科学转化医学》(Science Translational Medicine)杂志上发表了这项研究成果。
Some pharmaceutical companies are experimenting with other types of additives with the aim of short-circuiting bacteria's defenses.
Researchers at Merck & Co., in Whitehouse Station, N.J., are targeting an enzyme called beta-lactamase that lives in certain bacteria and neutralizes antibiotics sent to destroy them. By adding an enzyme-inhibiting agent called MK-7655 to the antibiotic imipenem, researchers managed to kill about 97% of a type of antibiotic-resistant bacteria that causes urinary-tract infections and pneumonia, according to Nicholas Kartsonis, head of clinical development of antibacterial, antifungals and non-hepatology viruses at Merck Research Labs.
美国新泽西州怀特豪斯站(Whitehouse Station, N.J.)的默克公司(Merck & Co.)研究人员现在把目标锁定在一种名为β-内胺的上面，这种?栖身于某些细菌中并让奉命去摧毁它们的抗生素失去效力。按照默克研究实验室(Merck Research Labs)抗菌素、抗真菌剂和非肝胆疾病病毒临床开发负责人尼古拉斯·卡特索尼斯(Nicholas Kartsonis)的说法，通过在抗生素亚胺培南中加入一种名为MK-7655的抑制剂，研究人员成功地将一种引起尿路感染和肺炎的抗药性细菌杀灭了97%。
Synthetic Biologics Inc. is taking advantage of beta-lactamase's ability to neutralize antibiotics by adding a modified version of the enzyme to the drugs. The aim is to prompt the antibiotic to break down when it reaches the bowel, where side effects and drug resistance for bacteria called Clostridium difficile, or C. difficile, develops, but to leave the antibiotic intact in the bloodstream. The process should allow larger doses of antibiotics to be administered without the patient suffering typical side effects such as gastrointestinal problems, says John Monahan, who heads research and development for the Rockville, Md.-based company.
合成生物制剂公司(Synthetic Biologics Inc.)通过在药物里添加一种经过改良的β-内胺来发挥这种?中和抗生素的能力，其目的是在抗生素到达肠道（一种名为艰难梭状芽孢杆菌(Clostridium difficile, or C. difficile)的细菌会在此产生副作用和抗药性）时促进抗生素的分解，但却会让血液中的抗生素毫发无损。总部位于马里兰州罗克维尔(Rockville, Md.)的这家公司负责研究与开发的约翰·莫纳汉(John Monahan)说，这种方法将使病人能够服用更大剂量的抗生素而不会引起胃肠性问题等典型副作用。
C. difficile, which causes life-threatening diarrhea and is blamed for 14,000 deaths a year, can spread rapidly in hospital patients on antibiotics. Although there are drugs to treat C. difficile, the bacteria are resistant to many antibiotics used to treat other types of infections.
Antibiotics naturally lose their effectiveness over time as bacteria populations build up resistance, and new drugs need to be continually developed to take their place. But antibiotic development by pharmaceutical companies slowed sharply after about 1990, in part because they are less profitable than other drugs used to treat chronic diseases. Compounding the problem has been an overuse of antibiotics in people and farm animals, which has accelerated the creation of antibiotic-resistant germs.
'Antibiotics have a finite lifetime because resistance is inevitable,' says Michael Fischbach, a bioengineering and therapeutic sciences professor at the University of California, San Francisco. 'Therefore, there's always a need to innovate.'
“抗生素的寿命是有限的，因为抗性的产生不可避免，”旧金山加利福尼亚大学(University of California)的生物工程及治疗科学教授迈克尔·菲施巴赫(Michael Fischbach)说，“因此，永远都会有推陈出新的需要。”
Bacteria have ways of defending themselves against other bacteria, and most antibiotics are derived from the toxins they use. Identifying and developing new antibiotics is a long and slow process. Now, scientists are able to more efficiently scrutinize microbes for undiscovered antibiotics by sequencing their genomes and then using computer analysis to look for gene patterns that suggest a new antibiotic recipe. Typically, antibiotics are encoded by anywhere from 10 to 40 genes.
Sean Brady, head of the Laboratory of Genetically Encoded Small Molecules at Rockefeller University in New York, and his colleagues recently zeroed in on half a dozen gene sequences. The team found that the genes were encoded for toxins that appeared in lab testing to be active against pathogens resistant to the antibiotic vancomycin, which is commonly used to treat infections in the gut. The research was published in the Proceedings of the National Academy of Science in June.
纽约洛克菲勒大学(Rockefeller University) 小分子基因编码实验室(the Laboratory of Genetically Encoded Small Molecules)负责人肖恩·布雷迪(Sean Brady)和他的同事最近瞄准了六个基因序列。该团队发现，在实验室试验中似乎可以积极抑制耐万古霉素（普遍用于治疗肠道感染的抗生素）病原体的毒素基因已经完成了编码。这项研究发表在六月的《美国国家科学院院刊》(the Proceedings of the National Academy of Science)上。
Whether the antibiotic will be useful in treating people remains to be seen, says Dr. Brady. The main problem with identifying new antibiotics isn't that they don't work, but that they cause severe side effects or toxicity, drug makers say.
Another group of researchers, headed by Dr. Fischbach at the University of California, has found a handful of new antibiotics that kill methicillin-resistant Staphylococcus aureus, or MRSA, by sequencing genomes of bacteria found in the environment. MRSA can cause a range of illnesses from skin infections to pneumonia and bloodstream infections.
An unusual strategy doesn't aim to kill bacteria at all, but rather to make them less harmful. Since bacteria only cause infections when their population has reached a certain threshold, called a quorum, researchers are looking for ways to disrupt the chemical signals the bugs use to communicate with each other. Another approach aims to neutralize toxins or disrupt other signaling molecules that are necessary for bacteria to be infectious.
'We don't challenge them to a duel but basically confuse them into not causing infection,' says Gerry Wright, a professor of biochemistry and biomedical sciences at McMaster University in Hamilton, Ontario.
“我们并不挑起和它们的决斗，而主要是引起它们的混乱，使其不会引起感染，”加拿大安大略省哈密尔顿市(Hamilton, Ontario)麦克马斯特大学(McMaster University)的生物化学及生物医学教授格里·赖特(Gerry Wright)说。
Dr. Brady and his team at Rockefeller University demonstrated that disrupting a cluster of genes reduced the virulence of a microbe that causes infection affecting the lungs, bones and joints. The researchers published the work late last year in the Journal of the American Chemical Society.
洛克菲勒大学的布雷迪和他的团队证明，对一组基因加以干扰降低了一种能够引起肺部、骨骼和关节感染的细菌的毒性。这队研究人员去年年底将他们的研究发表在《美国化学学会会志》(Journal of the American Chemical Society)上。