Malonyl-CoA:acyl carrier protein transacylase (FabD), being an essential enzyme of the FAS II pathway, is an attractive target for developing broad-spectrum antibiotics. It performs initiation reaction to form malonyl-ACP, which is a key building block in fatty acid biosynthesis. In this study, we have characterized the FabD from drug-resistant pathogen Moraxella catarrhalis (McFabD). More importantly, we have shown the binding of McFabD with three new compounds from the class of aporphine alkaloids. ITC based binding studies have shown that apomorphine is binding to McFabD with a stronger affinity (K_D = 4.87 μ&Mgr) as compared to boldine (K_D = 7.19 μ&Mgr) and magnoflorine (K_D = 11.7 μ&Mgr). The possible mechanism of fluorescence quenching is found to be static with K_q values higher than 10¹⁰, which was associated with the ground state complex formation of aporphine alkaloids with McFabD. Conformational changes observed in the secondary and tertiary structure marked by the loss of helical content during the course of interactions. Molecular docking based studies have predicted the binding mode of aporphine alkaloids and it is found that these compounds are interacting in a similar fashion as known inhibitor corytuberine is interacting with McFabD. The analysis of docking poses have revealed that His 210, Leu102, Gln19, Ser101 and Arg 126 are critical residues which may play important role in binding. The growth inhibition assay has shown that apomorphine has better MIC value (4–8 μg/ml) against Moraxella catarrhalis as compared to boldine and magnoflorine. Therefore, the current study suggests that aporphine alkaloids can act as antibacterial agents and possible target of these compounds could be FabD enzyme from the FAS II pathway, and apomorphine scaffold will be more suitable among these compounds for potential development of antibacterial agents.

丙二酰辅酶A：酰基载体蛋白转酰酶（FabD）是FAS II途径的必需酶，是开发广谱抗生素的有吸引力的靶标。它进行引发反应以形成丙二酸-ACP，丙二酸-ACP是脂肪酸生物合成的关键组成部分。在这项研究中，我们已经从耐药性病原体卡他莫拉菌（McFabD）中鉴定了FabD。更重要的是，我们已经显示了McFabD与三种新的化合物之间的结合，这些化合物来自于Aph的生物碱。基于ITC结合研究表明，阿扑吗啡与较强的亲和力（K结合McFabD _d  = 4.87μ＆经理）相比boldine（K _d  = 7.19μ＆经理）和木兰花碱（K _d = 11.7μ＆Mgr）。发现荧光猝灭的可能机制是静态的，且K _q值高于10 ¹⁰，这与McFabD形成的鸟嘌呤生物碱基态复合物有关。在相互作用过程中，在二级和三级结构中观察到的构象变化以螺旋含量的损失为特征。基于分子对接的研究已预测了阿啡啡碱生物碱的结合模式，并且发现这些化合物的相互作用方式与已知的抑制剂胭脂碱与McFabD相互作用的方式相似。对接姿势的分析表明，His 210，Leu102，Gln19，Ser101和Arg 126是关键残基，可能在结合中起重要作用。生长抑制试验表明，阿扑吗啡对卡他莫拉菌具有更好的MIC值（4–8μg/ ml）与丁香和木兰素相比。因此，目前的研究表明，阿扑吗啡生物碱可以作为抗菌剂，并且这些化合物的可能靶标可能是来自FAS II途径的FabD酶，而阿扑吗啡支架将更适合这些化合物中潜在的抗菌剂开发。