Soojhawon Iswarduth, Pattabiraman Nagarajan, Tsang Arthur, Roth Amanda L, Kang Ellen, Noble Schroeder M
Wound Infections Department, Bacterial Diseases Branch, Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA.
MolBox LLC, Silver Spring, MD 20910, USA.
Bioorg Med Chem. 2017 Oct 15;25(20):5477-5482. doi: 10.1016/j.bmc.2017.08.014. Epub 2017 Aug 9.
The recent emergence of multidrug-resistant Acinetobacter baumannii strains and the non-efficacy of currently available antibiotics against such infections have led to an urgent need for the development of novel antibacterials. In an effort to address this problem, we have identified three novel inhibitors, namely, D5, D12 and D6 using in silico screening with a homology model of the outer membrane protein W2 (OmpW2) from A. baumannii, as the proposed new drug target. OmpW is an eight-stranded β-barrel protein involved in the transport of hydrophobic molecules across the outer membrane and maintenance of homeostasis under cellular stress. The antimicrobial activities of compounds D5, D12 and D6 were evaluated against a panel of clinical isolates of A. baumannii strains. These compounds inhibited the growth of the strains with minimum inhibitory concentration (MIC) ranges of 1-32μg/mL. Time-kill kinetic studies with the highly virulent and multidrug-resistant strain, A. baumannii 5075, indicated that D6 exhibited the highest bactericidal activity asa≥3log CFU/mL (99.9%) reduction in colony count from the initial inoculum was observed after 30min incubation. D5 and D12 reduced at least 1log CFU/mL (90%) of the initial inoculum after 24h. In conclusion, these three lead inhibitors have provided two distinct chemical scaffolds for further analog design and optimizations, using chemical synthesis, to develop more potent inhibitors of the pathogen.
多重耐药鲍曼不动杆菌菌株的近期出现以及现有抗生素对此类感染的无效性导致迫切需要开发新型抗菌药物。为了解决这个问题，我们通过计算机筛选，以鲍曼不动杆菌外膜蛋白W2（OmpW2）的同源模型作为拟议的新药物靶点，鉴定出了三种新型抑制剂，即D5、D12和D6。OmpW是一种由八条链组成的β桶状蛋白，参与疏水分子跨外膜的转运以及细胞应激下的内环境稳态维持。对一组鲍曼不动杆菌临床分离株评估了化合物D5、D12和D6的抗菌活性。这些化合物抑制菌株生长的最低抑菌浓度（MIC）范围为1-32μg/mL。对高毒力和多重耐药菌株鲍曼不动杆菌5075进行的时间-杀菌动力学研究表明，D6表现出最高的杀菌活性，孵育30分钟后，初始接种物的菌落计数减少≥3log CFU/mL（99.9%）。D5和D12在24小时后使初始接种物减少至少1log CFU/mL（90%）。总之，这三种先导抑制剂为进一步的类似物设计和优化提供了两种不同的化学支架，利用化学合成来开发更有效的病原体抑制剂。
