Salifu Elliasu Y, Agoni Clement, Olotu Fisayo A, Soliman Mahmoud E S
Molecular Bio-computation and Drug Design Laboratory, School of Health Sciences, University of KwaZulu-Natal, Westville Campus, Durban, 4001, South Africa.
Molecular Bio-computation and Drug Design Laboratory, School of Health Sciences, University of KwaZulu-Natal, Westville Campus, Durban, 4001, South Africa.
Comput Biol Chem. 2020 Apr;85:107204. doi: 10.1016/j.compbiolchem.2020.107204. Epub 2020 Jan 13.
Bedaquiline (BDQ) has demonstrated formidable bactericidal activity towards Mycobacterium tuberculosis (Mtb) in the treatment of multi-drug resistant (MDR) and extensively drug resistant (XDR) tuberculosis (TB). BDQ elicits its therapeutic function by halting the ionic shuttle of Mtb via mycobacterial FF ATP-synthase blockade. However, triple mutations (L59 V, E61D and I66 M) at the ligand-binding cavity characterize emerging BDQ-resistant strains thereby restraining the potentials embedded in this anti-microbial compound, particularly in MDR/XDR-TB therapy. In this report, the effects of these triple mutations on BDQ-Mtb FF ATP-synthase binding were investigated using molecular dynamics, free energy binding and residue interaction network (RIN) analyses. The highlight of our findings is the drastic reduction in BDQ binding affinity (ΔG) in the triple mutant protein, which was caused by a systemic loss in high-affinity interactions primarily mediated by L59, E61 and I66. While wildtype L59 and I66 formed pi-alkyl interactions with BDQ at the FF ATP-synthase binding site, E61 elicited conventional (O--HO) bond. Upon transition, V59 and I66 were devoid of interactions with BDQ while D61 existed in a weaker non-conventional (C--HO) bond. Likewise, these mutations distorted the binding site and overall structural architecture of FF ATP-synthase in the presence of BDQ as revealed by the RIN and conformational analyses. Insights from this study could serve as a starting point for the structure-based design of novel inhibitors that could overcome mutational setbacks posed by BDQ-resistant strains in MDR/XDR-TB treatment.
贝达喹啉（BDQ）在治疗耐多药（MDR）和广泛耐药（XDR）结核病（TB）方面已显示出对结核分枝杆菌（Mtb）具有强大的杀菌活性。BDQ通过阻断分枝杆菌FF ATP合酶来停止Mtb的离子穿梭，从而发挥其治疗作用。然而，配体结合腔的三重突变（L59V、E61D和I66M）是新出现的BDQ耐药菌株的特征，从而限制了这种抗菌化合物的潜力，特别是在MDR/XDR-TB治疗中。在本报告中，使用分子动力学、自由能结合和残基相互作用网络（RIN）分析研究了这些三重突变对BDQ-Mtb FF ATP合酶结合的影响。我们研究结果的亮点是三重突变蛋白中BDQ结合亲和力（ΔG）的急剧降低，这是由主要由L59、E61和I66介导的高亲和力相互作用的系统性丧失引起的。野生型L59和I66在FF ATP合酶结合位点与BDQ形成π-烷基相互作用，而E61形成传统的（O--HO）键。转变后，V59和I66与BDQ没有相互作用，而D61存在于较弱的非传统（C--HO）键中。同样，如RIN和构象分析所示，这些突变在存在BDQ的情况下扭曲了FF ATP合酶的结合位点和整体结构架构。这项研究的见解可以作为基于结构设计新型抑制剂的起点，这些抑制剂可以克服BDQ耐药菌株在MDR/XDR-TB治疗中造成的突变障碍。
