PDF(Pubmed)
Abstract：
Staphylococcus aureus is a common human pathogen. Methicillin-resistant Staphylococcus aureus (MRSA) infections pose significant and challenging therapeutic difficulties. MRSA often acquires the non-native gene PBP2a, which results in reduced susceptibility to β-lactam antibiotics, thus conferring resistance. PBP2a has a lower affinity for methicillin, allowing bacteria to maintain peptidoglycan biosynthesis, a core component of the bacterial cell wall. Consequently, even in the presence of methicillin or other antibiotics, bacteria can develop resistance. Due to genes responsible for resistance, S. aureus becomes MRSA. The fundamental premise of this resistance mechanism is well-understood. Given the therapeutic concerns posed by resistant microorganisms, there is a legitimate demand for novel antibiotics. This review primarily focuses on PBP2a scaffolds and the various screening approaches used to identify PBP2a inhibitors. The following classes of compounds and their biological activities are discussed: Penicillin, Cephalosporins, Pyrazole-Benzimidazole-based derivatives, Oxadiazole-containing derivatives, non-β-lactam allosteric inhibitors, 4-(3H)-Quinazolinones, Pyrrolylated chalcone, Bis-2-Oxoazetidinyl macrocycles (β-lactam antibiotics with 1,3-Bridges), Macrocycle-embedded β-lactams as novel inhibitors, Pyridine-Coupled Pyrimidinones, novel Naphthalimide corbelled aminothiazoximes, non-covalent inhibitors, Investigational-β-lactam antibiotics, Carbapenem, novel Benzoxazole derivatives, Pyrazolylpyridine analogues, and other miscellaneous classes of scaffolds for PBP2a. Additionally, we discuss the penicillin-binding protein, a crucial target in the MRSA cell wall. Various aspects of PBP2a, bacterial cell walls, peptidoglycans, different crystal structures of PBP2a, synthetic routes for PBP2a inhibitors, and future perspectives on MRSA inhibitors are also explored.
摘要：
金黄色葡萄球菌是人类常见的病原体。耐甲氧西林金黄色葡萄球菌(MRSA)感染造成显著且具有挑战性的治疗困难。MRSA经常获得非天然基因PBP2a，这导致对β-内酰胺抗生素的敏感性降低，从而赋予抵抗。PBP2a对甲氧西林的亲和力较低，允许细菌维持肽聚糖的生物合成，细菌细胞壁的核心部件。因此,即使在存在甲氧西林或其他抗生素的情况下，细菌可以产生抗药性。由于负责抗性的基因，金黄色葡萄球菌变成MRSA。这种抗性机制的基本前提是很好理解的。鉴于耐药微生物带来的治疗问题，对新型抗生素有合法需求。这篇综述主要集中在PBP2a支架和用于鉴定PBP2a抑制剂的各种筛选方法。讨论了以下几类化合物及其生物活性：青霉素，头孢菌素,吡唑-苯并咪唑基衍生物，含恶二唑的衍生物，非β-内酰胺变构抑制剂，4-(3H)-喹唑啉酮,吡喃化查尔酮，双-2-氧氮杂环丁烷基大环（含1,3-桥的β-内酰胺抗生素），大环包埋的β-内酰胺作为新型抑制剂，吡啶偶联嘧啶酮,新型萘酰亚胺胶状氨基噻唑肟，非共价抑制剂，研究性β-内酰胺抗生素，Carbapenem,新型苯并恶唑衍生物，吡唑基吡啶类似物，以及其他用于PBP2a的杂类脚手架。此外,我们讨论青霉素结合蛋白，MRSA细胞壁中的关键靶标。PBP2a的各个方面，细菌细胞壁，肽聚糖，不同晶体结构的PBP2a，PBP2a抑制剂的合成路线，并探讨了MRSA抑制剂的未来前景。
