Characterizing the Antimicrobial Activity of N2,N4-Disubstituted Quinazoline-2,4-Diamines toward Multidrug-Resistant Acinetobacter baumannii
Characterizing the Antimicrobial Activity of N2,N4-Disubstituted Quinazoline-2,4-Diamines toward Multidrug-Resistant Acinetobacter baumannii
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DOI：
10.1128/aac.00059-17
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发表时间：
2017-06-01
影响因子：
4.9
通讯作者：
Shaw, Lindsey N.
中科院分区：
文献类型：
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作者：
Fleeman, Renee;Van Horn, Kurt S.;Shaw, Lindsey N.
我们以前报道了一系列N-2，N-4-二取代喹唑啉-2，4-二胺作为二氢叶酸还原酶抑制剂，对耐甲氧西林金黄色葡萄球菌（MRSA）菌株具有有效的体外和体内抗菌活性。在这项工作中，我们扩展了我们以前的研究，革兰氏阴性病原体鲍曼不动杆菌。我们确定优化的N-2，N-4-二取代喹唑啉-2，4-二胺对多药耐药A.当6-位被卤素或烷基取代基取代时，鲍曼不动杆菌应变。这些试剂显示出有效的抗菌活性，MIC低至0.5 μ M，同时证明是强杀菌的。有趣的是，这些化合物也具有潜在的抗氧化膜活性，消除90%的细胞内的生物膜或附近的MIC。使用连续传代试验，我们观察到一个有限的能力，对这些分子（MIC增加4倍）相比，现有的叶酸合成抑制剂，如甲氧苄啶（64倍增加）和磺胺甲恶唑（128倍增加）的耐药性发展。我们还确定了对人类细胞的有限毒性，50%致死剂量（LD（50））为
We previously reported a series of N-2,N-4-disubstituted quinazoline-2,4diamines as dihydrofolate reductase inhibitors with potent in vitro and in vivo antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA) strains. In this work, we extended our previous study to the Gram-negative pathogen Acinetobacter baumannii. We determined that optimized N-2,N-4-disubstituted quinazoline-2,4-diamines are strongly antibacterial against multidrug-resistant A. baumannii strains when the 6-position is replaced with a halide or an alkyl substituent. Such agents display potent antibacterial activity, with MICs as low as 0.5 mu M, while proving to be strongly bactericidal. Interestingly, these compounds also possess the potential for antibiofilm activity, eradicating 90% of cells within a biofilm at or near MICs. Using serial passage assays, we observed a limited capacity for the development of resistance toward these molecules (4-fold increase in MIC) compared to existing folic acid synthesis inhibitors, such as trimethoprim (64-fold increase) and sulfamethoxazole (128-fold increase). We also identified limited toxicity toward human cells, with 50% lethal doses (LD(50)s) of