Antimicrobial resistance (AMR) is a major health problem worldwide, because of ability of bacteria, fungi and viruses to evade known therapeutic agents used in treatment of infections. Aryldiketo acids (ADK) have shown antimicrobial activity against several resistant strains including Gram-positive Staphylococcus aureus bacteria. Our previous studies revealed that ADK analogues having bulky alkyl group in ortho position on a phenyl ring have up to ten times better activity than norfloxacin against the same strains. Rational modifications of analogues by introduction of hydrophobic substituents on the aromatic ring has led to more than tenfold increase in antibacterial activity against multidrug resistant Gram positive strains.

To elucidate a potential mechanism of action for this potentially novel class of antimicrobials, several bacterial enzymes were identified as putative targets according to literature data and pharmacophoric similarity searches for potent ADK analogues. Among the seven bacterial targets chosen, the strongest favorable binding interactions were observed between most active analogue and S. aureus dehydrosqualene synthase and DNA gyrase. Furthermore, the docking results in combination with literature data suggest that these novel molecules could also target several other bacterial enzymes, including prenyl-transferases and methionine aminopeptidase. These results and our statistically significant 3D QSAR model could be used to guide the further design of more potent derivatives as well as in virtual screening for novel antibacterial agents.

由于细菌，真菌和病毒逃避用于治疗感染的已知治疗剂的能力，因此抗菌素耐药性（AMR）是全球范围内的主要健康问题。芳基二酮酸（ADK）对几种耐药菌株（包括革兰氏阳性金黄色葡萄球菌）表现出抗菌活性。我们先前的研究表明，在相同环上，苯环上邻位具有大体积烷基的ADK类似物的活性比诺氟沙星高出十倍。通过在芳香环上引入疏水性取代基对类似物进行合理的修饰，已使针对多药耐药革兰氏阳性菌株的抗菌活性提高了十倍以上。

为了阐明这种潜在的新型抗菌剂的潜在作用机理，根据文献数据和药效学相似性搜索，对有效的ADK类似物鉴定了几种细菌酶作为推定的靶标。在选择的七个细菌靶标中，最活跃的类似物与金黄色葡萄球菌之间观察到最强的有利结合相互作用脱氢角鲨烯合酶和DNA旋转酶。此外，对接结果与文献数据相结合表明，这些新型分子还可以靶向其他几种细菌酶，包括异戊二烯基转移酶和甲硫氨酸氨基肽酶。这些结果和我们具有统计意义的3D QSAR模型可用于指导更有效的衍生物的进一步设计，以及用于新型抗菌剂的虚拟筛选。