Department of Bioinformatics, VMKV Engineering College, Vinayaka Missions University, Salem 636 308, India.
Infect Genet Evol. 2012 Dec;12(8):1899-910. doi: 10.1016/j.meegid.2012.08.013. Epub 2012 Sep 6.
Leprosy remains a major public health problem, since single and multi-drug resistance has been reported worldwide over the last two decades. In the present study, we report the novel multi-targeted therapy for leprosy to overcome multi drug resistance and to improve therapeutic efficacy. If multiple enzymes of an essential metabolic pathway of a bacterium were targeted, then the therapy would become more effective and can prevent the occurrence of drug resistance. The MurC, MurD, MurE and MurF enzymes of peptidoglycan biosynthetic pathway were selected for multi targeted therapy. The conserved or class specific active site residues important for function or stability were predicted using evolutionary trace analysis and site directed mutagenesis studies. Ten such residues which were present in at least any three of the four Mur enzymes (MurC, MurD, MurE and MurF) were identified. Among the ten residues G125, K126, T127 and G293 (numbered based on their position in MurC) were found to be conserved in all the four Mur enzymes of the entire bacterial kingdom. In addition K143, T144, T166, G168, H234 and Y329 (numbered based on their position in MurE) were significant in binding substrates and/co-factors needed for the functional events in any three of the Mur enzymes. These are the probable residues for designing newer anti-leprosy drugs in an attempt to reduce drug resistance.
麻风病仍然是一个主要的公共卫生问题，因为在过去的二十年中，全世界都报告了单一和多药耐药性。在本研究中，我们报告了一种新的麻风病多靶点治疗方法，以克服多药耐药性并提高治疗效果。如果针对细菌必需代谢途径的多个酶，则该治疗将更加有效，并可以防止耐药性的发生。选择肽聚糖生物合成途径的 MurC、MurD、MurE 和 MurF 酶进行多靶点治疗。使用进化痕迹分析和定点诱变研究预测对功能或稳定性很重要的保守或类特异性活性位点残基。在至少三个 Mur 酶（MurC、MurD、MurE 和 MurF）中存在十个这样的残基。在十个残基中，G125、K126、T127 和 G293（根据 MurC 中的位置编号）在整个细菌王国的四个 Mur 酶中均保守。此外，K143、T144、T166、G168、H234 和 Y329（根据 MurE 中的位置编号）在三个 Mur 酶中的任何一个中结合底物和/辅助因子的功能事件中都很重要。这些可能是设计新型抗麻风病药物的候选残基，以试图降低耐药性。
