Biswas Raju, Panja Anindya Sundar, Bandopadhyay Rajib
1Department of Botany, UGC-Center of Advanced Study, The University of Burdwan, Golapbag, Burdwan, West Bengal 713104 India.
Department of Botany, Syamsundar College, Shyamsundar, Burdwan, West Bengal 713424 India.
Indian J Microbiol. 2019 Jun;59(2):254-259. doi: 10.1007/s12088-019-00781-6. Epub 2019 Jan 22.
The treatment of bacterial infections is becoming increasingly ineffective due to rapid mutation which leads to antibiotic resistant and resistant bacteria become more prevalent. As a result the existing antibiotics are gradually obsolete and again new drugs are needed to be designed for the same threat. However, the prediction of evolutionary processes/antibiotic resistance is uncertain. Still, the understanding of mode of evolution of resistance in bacteria is a determining step in the preclinical development of new antibiotics, because drug developers assess the risk of resistance arising against a drug during preclinical development. Multidrug efflux pump systems play an important role for making multidrug resistance to a range of clinically important antibiotics in gram-negative bacteria like , which lower the intracellular drug concentration by exporting incoming antibiotics across the membranes. We tried to show that the wild type susceptible bacteria modified its genetic makeup at mutational hotspots under stress. This strain may either become multidrug resistant or remain susceptible depending on position of amino acid changes in regulatory proteins of efflux pump. Multidrug resistant strain made significant changes at the amino acid positions, 103rd (G → A) and 126th (E → V) through the mutation on the nucleotide position of 308th (G → C); both 377th (A → T) and 378th (G → T), respectively in , a repressor of mexAB-oprM efflux pump. This mutant protein showed low affinity with their operator. But the alteration at 103th position (G → A) in may provide almost similar structural and functional stability as wild type. It was found that mutation was seemed to be well regulated within the limit and position specific under stress which might be back to its original form by supplying counter stress unless addition or deletion takes place.
由于细菌的快速突变导致抗生素耐药性，耐药细菌越来越普遍，细菌感染的治疗正变得越来越无效。结果，现有的抗生素逐渐过时，因此需要设计新的药物来应对同样的威胁。然而，进化过程/抗生素耐药性的预测是不确定的。尽管如此，了解细菌耐药性的进化模式是新抗生素临床前开发的决定性步骤，因为药物研发人员在临床前开发过程中评估药物产生耐药性的风险。多药外排泵系统在革兰氏阴性菌（如 ）对一系列临床重要抗生素产生多药耐药性方面发挥着重要作用，它通过将进入的抗生素跨膜输出，降低细胞内药物浓度。我们试图表明，野生型敏感细菌在压力下会在突变热点改变其基因组成。根据外排泵调节蛋白中氨基酸变化的位置，该菌株可能会变成多药耐药性或保持敏感。多药耐药菌株通过在第308位核苷酸（G→C）发生突变，在第103位（G→A）和第126位（E→V）氨基酸位置发生了显著变化；分别在mexAB-oprM外排泵的阻遏物 中的第377位（A→T）和第378位（G→T）。这种突变蛋白与其操纵子的亲和力较低。但 在第103位（G→A）的改变可能提供与野生型几乎相似的结构和功能稳定性。研究发现，突变似乎在压力下受到良好的限制且具有位置特异性，除非发生添加或缺失，否则通过施加反压力可能会恢复到其原始形式。
