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

对抗革兰氏阴性细菌病原体的碳青霉烯类耐药性威胁

• 批准号: G1100135/1
• 负责人: Timothy Walsh
• 金额: $ 127.42万
• 依托单位: CARDIFF UNIVERSITY
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2011
• 资助国家: 英国
• 起止时间: 2011 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=G1100135%2F1
• 关键词: Combatting; threat; carbapenem; resistance; Gram

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.

随着易感人群的数量（例如老年人，移植或癌症化学疗法患者）增加，医院可获得的感染（HAIS）的衰老人数增加。由抗生素耐药菌引起的HAI很难治疗，因此更危险。尽管MRSA（耐甲氧西林金黄色葡萄球菌）是HAI的最臭名昭著的原因，但所谓的革兰氏阴性细菌（例如Escherichia Coli）也是每年成千上万的海斯。这些生物引起的对抗HAI的最重要的抗生素是β-内酰胺药物，其中青霉素是最著名的。由于革兰氏阴性细菌已经对大多数其他抗生素具有抗药性，因此称为碳青霉烯（最强大的β-内酰胺）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，革兰氏阴性细菌中的碳青霉烯耐药性相对较少，并且通常在细菌中遇到的碳青霉含量比大肠杆菌及其亲戚少的细菌遇到。然而，随着最近发现的几种革兰氏阴性菌菌株（携带一个名为NDM-1的基因）的碳苯甲菌株正在迅速扩散，这种情况现在已经发生了变化。这是一个重要的问题，因为尽管几种新的抗生素对MRSA有效，但尚无用于抗抗生素革兰氏阴性细菌的新药物。因此，耐碳青霉烯的细菌感染很难治疗。我们的目的是为抗碳青霉烯剂引起的革兰氏阴性细菌开发新的治疗方法。可以通过将青霉素与阻断耐药机制结合的药物结合来治疗耐青霉素的革兰氏阴性细菌。但是，尚未证明可以阻止NDM-1（或相关基因的活性）的活性。我们的团队结合了来自英国和加拿大的化学家，生物化学家，大学和医院的微生物学家，将设计，制造和测试分子，而不是阻止NDM-1等碳青霉烯耐药机制的功能，因此，这将恢复碳青霉苯甲部杀死抵抗力的革兰氏阴性细菌的能力。对这些生物的可靠活性的抗生素将改变许多HAI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，特别是在医院中，并确定在我们的测试计划中使用的最重要类型。我们将进一步开发新方法来测试特定分子是否能够阻止NDM-1的功能。测试如何阻止NDM-1的新方法和资源也将使更广泛的科学界的努力受益，以克服抗碳青霉烯的HAI的威胁。