Combatting the threat of carbapenem resistance in Gram-negative bacterial pathogens

随着老龄化人口中易感人群(如老年、移植或癌症化疗患者)数量的增加，医院获得性感染(HAI)的重要性与日俱增。由抗药性细菌引起的禽流感更难治疗，因此更危险。虽然耐甲氧西林金黄色葡萄球菌(MRSA)是HAI最臭名昭著的原因，但所谓的革兰氏阴性细菌，如大肠杆菌，也是每年数千起HAI的原因。在对抗由这些细菌引起的人类免疫缺陷病毒方面，最重要的抗生素是β-内酰胺类药物，其中青霉素是最知名的。由于革兰氏阴性菌已经对大多数其他抗生素产生抗药性，被称为碳青霉烯类(最有效的β-内酰胺类)的药物现在是用于治疗这些感染的最重要的抗生素。幸运的是，直到最近，革兰氏阴性细菌对碳青霉烯类抗生素的耐药性还相对较少，而且通常在引起HAI的细菌中比大肠杆菌及其近亲更少。然而，随着最近发现几种革兰氏阴性细菌(携带一种名为NDM-1的基因)的碳青霉烯耐药菌株正在全球迅速传播，这种情况现在已经改变。这是一个非常令人担忧的问题，因为虽然有几种新的抗生素对MRSA有效，但到目前为止还没有针对耐药的革兰氏阴性细菌的新药。因此，耐碳青霉烯类细菌的感染很难治疗。我们的目标是开发一种新的治疗方法，治疗由碳青霉烯类耐药的革兰氏阴性细菌引起的血吸虫病。对青霉素耐药的革兰氏阴性细菌可以通过青霉素与一种阻断耐药机制的药物相结合来治疗。然而，尚未证明有可能阻断NDM-1的活性(或相关基因的活性)。我们的团队由来自英国和加拿大的化学家、生物化学家以及大学和医院的微生物学家组成，他们将设计、制造和测试分子，以阻止像NDM-1这样的碳青霉烯耐药机制的功能，从而恢复碳青霉烯类抗生素杀死耐药革兰氏阴性细菌的能力。一种对这些微生物具有可靠活性的抗生素将改变许多HAIS患者的前景。作为这项工作的一部分，我们还将监测携带NDM-1和类似基因的细菌的传播情况，特别是在医院中的传播情况，并确定在我们的检测计划中使用的最重要类型。我们将进一步开发新的方法来测试特定的分子是否能够阻断NDM-1的功能。用于测试如何阻止NDM-1的新方法和资源也将有利于更广泛的科学界克服碳青霉烯耐药禽流感威胁的努力。

Hospital-acquired infections (HAIs) are growing in importance as the numbers of susceptible individuals (e.g. elderly, transplant or cancer chemotherapy patients) increase in aging populations. HAIs caused by antibiotic-resistant bacteria are more difficult to treat and consequently more dangerous. While MRSA (methicillin-resistant Staphylococcus aureus) is the most notorious cause of HAIs, so-called Gram-negative bacteria, such as Escherichia coli, are also responsible for many thousands of HAIs each year. The most important antibiotics in the fight against HAIs caused by these organisms are the beta-lactam drugs, of which penicillin is the best known. Since Gram-negative bacteria have become resistant to most other antibiotics, drugs called carbapenems (the most powerful beta-lactams) are now the most important antibiotics used to treat these infections. Fortunately, until recently carbapenem resistance in Gram-negative bacteria has been relatively rare, and usually encountered in bacteria that cause fewer HAIs than E. coli and its relatives. However, this situation has now changed with the recent discovery that carbapenem-resistant strains of several Gram-negative bacteria (carrying a gene called NDM-1) are spreading rapidly worldwide. This is a significant concern because, while several new antibiotics are effective against MRSA, there are as yet no new drugs for antibiotic-resistant Gram-negative bacteria. Infections by carbapenem-resistant bacteria are consequently very hard to treat.We aim to develop a new treatment for HAIs caused by carbapenem-resistant Gram-negative bacteria. Penicillin-resistant Gram-negative bacteria can be treated by combining penicillin with a drug that blocks the mechanism of resistance. However, it has not yet proved possible to block the activity of NDM-1 (or that of related genes). Our team, which combines chemists, biochemists and university and hospital microbiologists from the U.K. and Canada, will design, make and test molecules than block the function of carbapenem-resistance mechanisms like NDM-1 and that consequently will restore the ability of carbapenems to kill resistant Gram-negative bacteria. An antibiotic that is reliably active against these organisms will transform the outlook for many patients with HAIs. As part of this work we will also monitor the spread, particularly in hospitals, of bacteria that carry NDM-1 and similar genes, and identify the most important types to use in our testing programme. We will further develop new methods to test whether particular molecules are able to block the function of NDM-1. New methods and resources for testing how to block NDM-1 will also benefit efforts in the wider scientific community to overcome the threat of carbapenem-resistant HAIs.