Structural Studies on 4,5-Disubstituted 2-Aminoimidazole-Based Biofilm Modulators that Suppress Bacterial Resistance to β-Lactams
Structural Studies on 4,5-Disubstituted 2-Aminoimidazole-Based Biofilm Modulators that Suppress Bacterial Resistance to β-Lactams
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DOI：
10.1002/cmdc.201200350
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发表时间：
2012-11-01
期刊：
影响因子：
3.4
通讯作者：
Melander, Christian
中科院分区：
文献类型：
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作者：
Su, Zhaoming;Yeagley, Andrew A.;Melander, Christian
成功地组装了4，5-二取代2-氨基咪唑三唑酰胺（2-AITA）缀合物库。在生物筛选后，发现这类小分子通过非杀微生物机制对耐甲氧西林金黄色葡萄球菌（MRSA）和多重耐药鲍曼不动杆菌（MDRAB）增强生物膜调节剂，活性浓度在低微摩尔范围内。该文库还进行了针对MRSA的β-内酰胺抗生素的协同作用和再敏感性研究。通过与苯唑西林（一种对青霉素酶具有抗性的β-内酰胺类抗生素）协同作用，鉴定了抑制MRSA抗生素抗性的先导化合物。对母体2-AITA化合物的进一步结构反应性关系（SAR）研究提供了2-氨基咪唑二酰胺（2-AIDA）缀合物，其与苯唑西林对MRSA的协同活性显著增加，使β-内酰胺抗生素的MIC值降低64倍。增加的抗生物膜活性不一定导致抗生素耐药性的抑制增加，这表明生物膜抑制和再敏感最有可能通过不同的机制发生。
A library of 4,5-disubstituted 2-aminoimidazole triazole amide (2-AITA) conjugates has been successfully assembled. Upon biological screening, this class of small molecules was discovered as enhanced biofilm regulators through non-microbicidal mechanisms against methicillin-resistant Staphylococcus aureus (MRSA) and multidrug-resistant Acinetobacter baumannii (MDRAB), with active concentrations in the low micromolar range. The library was also subjected to synergism and resensitization studies with beta-lactam antibiotics against MRSA. Lead compounds were identified that suppress the antibiotic resistance of MRSA by working synergistically with oxacillin, a beta-lactam antibiotic resistant to penicillinase. A further structureactivity relationship (SAR) study on the parent 2-AITA compound delivered a 2-aminoimidazole diamide (2-AIDA) conjugate with significantly increased synergistic activity with oxacillin against MRSA, decreasing the MIC value of the beta-lactam antibiotic by 64-fold. Increased anti-biofilm activity did not necessarily lead to increased suppression of antibiotic resistance, which indicates that biofilm inhibition and resensitization are most likely occurring via distinct mechanisms.