Preethi B, Ramanathan K
Industrial Biotechnology Division, School of Bio Sciences and Technology, VIT University, Vellore, 632014, Tamil Nadu, India.
Eur Biophys J. 2016 Jan;45(1):35-44. doi: 10.1007/s00249-015-1073-2. Epub 2015 Sep 2.
Nalidixic acid is an antibiotic drug used for treatment of Salmonellosis, a gastrointestinal infection. DNA gyrase subunit A (GyrA) of Salmonella typhimurium is the drug target for nalidixic acid. Resistance of GyrA to nalidixic acid, because of a point mutation in S. typhimurium, was recently reported. Substitution of Phe in place of Ser at locus 83 in GyrA of S. typhimurium has been experimentally associated with nalidixic acid resistance. Despite recent efforts, the mechanism of this resistance is not well understood. In this investigation we used computational techniques to address this shortcoming. Our results showed that contact with residue Arg 91 is certainly important for efficient binding of nalidixic acid to the target protein, and that mutation of this residue results in 180° rotation of the antibiotic in its binding pocket, around its own long axis. It is hoped these findings may enable development of new antibiotics against resistant forms of Salmonella.
萘啶酸是一种用于治疗沙门氏菌病（一种胃肠道感染）的抗生素药物。鼠伤寒沙门氏菌的DNA促旋酶亚基A（GyrA）是萘啶酸的药物靶点。最近有报道称，由于鼠伤寒沙门氏菌中的一个点突变，GyrA对萘啶酸产生了抗性。在鼠伤寒沙门氏菌GyrA的83位点用苯丙氨酸取代丝氨酸已通过实验证明与萘啶酸抗性有关。尽管最近进行了诸多努力，但这种抗性的机制仍未得到充分理解。在本研究中，我们使用计算技术来解决这一缺陷。我们的结果表明，与第91位残基精氨酸的接触对于萘啶酸与靶蛋白的有效结合肯定很重要，并且该残基的突变会导致抗生素在其结合口袋中围绕自身长轴旋转180°。希望这些发现能够推动针对耐药型沙门氏菌的新型抗生素的研发。
