Current Challenges in Antimicrobial Chemotherapy Focus on β-Lactamase Inhibition
Current Challenges in Antimicrobial Chemotherapy Focus on β-Lactamase Inhibition
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DOI：
10.2165/11318430-000000000-00000
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发表时间：
2010-01-01
期刊：
影响因子：
11.5
通讯作者：
Galleni, Moreno
中科院分区：
文献类型：
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作者：
Bebrone, Carine;Lassaux, Patricia;Galleni, Moreno
三种经典的β-内酰胺酶抑制剂(克拉维酸、他唑巴坦和舒巴坦)与β-内酰胺类抗菌药物联合使用是目前对抗β-内酰胺酶耐药最成功的策略。然而，这些抑制剂只有效地灭活A类β-内酰胺酶，并且抑制剂/抗菌组合的效率可能会受到几种机制的影响，例如产生自然耐药的B类或D类酶，高产AmpC酶，甚至产生进化的耐药A类酶。因此，迫切需要开发新型的抑制剂。对于丝氨酸活性酶(A、C和D类)，β-内酰胺环的衍生物，如6-β-卤代青霉烷酸酯、β-内酰胺砜、青霉烯类和草青霉烯类、单内酰胺类或三烯类似乎是设计有效分子(如AM-112和LK-157)的潜在起点。此外，一种很有前途的非β-内酰胺分子NXL-104目前正在临床开发中。相反，尽管已经描述了大量的潜在分子(联苯四唑、半胱氨酸多肽、巯基羧酸盐、琥珀酸衍生物等)，但仍未找到理想的金属β-内酰胺酶抑制剂(B类)。由于其催化机理中缺乏共价中间体，以及β-内酰胺衍生物通常作为底物而不是抑制剂的事实，使寻找这种抑制剂变得复杂。目前，最有前景的B类酶广谱抑制剂是具有螯合基团的分子(硫醇、羧酸盐等)。结合芳香族基团。这篇综述描述了已经被测试为潜在的β-内酰胺酶抑制剂的所有类型的分子，从而构成了β-内酰胺酶抑制剂发现的最新状况。
The use of the three classical beta-lactamase inhibitors (clavulanic acid, tazobactam and sulbactam) in combination with beta-lactam antibacterials is currently the most successful strategy to combat P-lactamase-mediated resistance. However, these inhibitors are efficient in inactivating only class A beta-lactamases and the efficiency of the inhibitor/antibacterial combination can be compromised by several mechanisms, such as the production of naturally resistant class B or class D enzymes, the hyperproduction of AmpC or even the production of evolved inhibitor-resistant class A enzymes. Thus, there is an urgent need for the development of novel inhibitors. For serine active enzymes (classes A, C and D), derivatives of the beta-lactam ring such as 6-beta-halogenopenicillanates, beta-lactam sulfones, penems and oxapenems, monobactams or trinems seem to be potential starting points to design efficient molecules (such as AM-112 and LK-157). Moreover, a promising non-beta-lactam molecule, NXL-104, is now under clinical development. In contrast, an ideal inhibitor of metallo-beta-lactamases (class B) remains to be found, despite the huge number of potential molecules already described (biphenyl tetrazoles, cysteinyl peptides, mercaptocarboxylates, succinic acid derivatives, etc.). The search for such an inhibitor is complicated by the absence of a covalent intermediate in their catalytic mechanisms and the fact that beta-lactam derivatives often behave as substrates rather than as inhibitors. Currently, the most promising broad-spectrum inhibitors of class B enzymes are molecules presenting chelating groups (thiols, carboxylates, etc.) combined with an aromatic group.This review describes all the types of molecules already tested as potential beta-lactamase inhibitors and thus constitutes an update of the current status in beta-lactamase inhibitor discovery.