Kashyap Aanchal, Singh Pankaj Kumar, Silakari Om
Molecular Modeling Lab (MML), Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, Punjab, 147002, India.
Molecular Modeling Lab (MML), Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, Punjab, 147002, India.
Tuberculosis (Edinb). 2018 Dec;113:43-54. doi: 10.1016/j.tube.2018.09.001. Epub 2018 Sep 8.
Tuberculosis (TB) is contagious in nature and immunocompromised patients have a higher probability of developing TB. The occurrence of drug resistance, has led to serious health concerns in the management of TB. In order to combat resistant tuberculosis there is an urgent need of identifying new drug targets and new drug combinations for the effective management and reduction in the duration of TB treatment. Targeting DNA gyrase that is involved in bacterial replication cycle, provides one rationale approach. Various fluoroquinolone based drugs have shown promising effect against DNA gyrase enzyme and in turn were successful in combat against MDR TB. However, GyrA domain mutations based resistance towards fluoroquinolones has put a question mark over current therapies for tuberculosis. Fluoroquinolones target GyrA domain of bacterial DNA gyrase therefore targeting DNA GyrB domain may overcome this resistance issue, establishing it as an attractive target. This review is a compilation of current research efforts on energy supplying domain of Mycobacterium tuberculosis that could provide breakthrough in development of more potent Mtb DNA GyrB inhibitors.
结核病本质上具有传染性,免疫功能低下的患者患结核病的概率更高。耐药性的出现给结核病的治疗带来了严重的健康问题。为了对抗耐药结核病,迫切需要确定新的药物靶点和新的药物组合,以有效管理结核病并缩短治疗时间。靶向参与细菌复制周期的DNA促旋酶提供了一种合理的方法。各种基于氟喹诺酮的药物已显示出对DNA促旋酶有良好效果,进而成功对抗多重耐药结核病。然而,基于GyrA结构域突变的对氟喹诺酮的耐药性给当前的结核病治疗带来了疑问。氟喹诺酮靶向细菌DNA促旋酶的GyrA结构域,因此靶向DNA GyrB结构域可能克服这一耐药问题,使其成为一个有吸引力的靶点。本综述汇编了目前关于结核分枝杆菌能量供应结构域的研究成果,这些研究可能为开发更有效的结核分枝杆菌DNA GyrB抑制剂带来突破。