Noguchi Memorial Institute for Medical Research, College of Health Sciences, University of Ghana, Legon, Accra P.O. Box LG 581, Ghana.
Pine Biotech, Inc., 1441 Canal St., New Orleans, LA 70112, USA.
Molecules. 2022 Dec 24;28(1):145. doi: 10.3390/molecules28010145.
The continual rise in sulfadoxine (SDX) resistance affects the therapeutic efficacy of sulfadoxine-pyrimethamine; therefore, careful monitoring will help guide its prolonged usage. Mutations in dihydropteroate synthase (dhps) are being surveilled, based on their link with SDX resistance. However, there is a lack of continuous analyses and data on the potential effect of molecular markers on the dhps structure and function. This study explored single-nucleotide polymorphisms (SNPs) in dhps that were isolated in Africa and other countries, highlighting the regional distribution and its link with structure. In total, 6336 genomic sequences from 13 countries were subjected to SNPs, haplotypes, and structure-based analyses. The SNP analysis revealed that the key SDX resistance marker, A437G, was nearing fixation in all countries, peaking in Malawi. The mutation A613S was rare except in isolates from the Democratic Republic of Congo and Malawi. Molecular docking revealed a general loss of interactions when comparing mutant proteins to the wild-type protein. During MD simulations, SDX was released from the active site in mutants A581G and A613S before the end of run-time, whereas an unstable binding of SDX to mutant A613S and haplotype A437A/A581G/A613S was observed. Conformational changes in mutant A581G and the haplotypes A581G/A613S, A437G/A581G, and A437G/A581G/A613S were seen. The radius of gyration revealed an unfolding behavior for the A613S, K540E/A581G, and A437G/A581G systems. Overall, tracking such mutations by the continuous analysis of dhps SNPs is encouraged. SNPs on the dhps structure may cause protein-drug function loss, which could affect the applicability of SDX in preventing malaria in pregnant women and children.
磺胺多辛（SDX）耐药性的持续上升影响了磺胺多辛-乙胺嘧啶的治疗效果；因此，仔细监测将有助于指导其长期使用。根据与 SDX 耐药性的关联，正在监测二氢叶酸合成酶（dhps）中的突变。然而，缺乏关于分子标记对 dhps 结构和功能的潜在影响的连续分析和数据。本研究探索了在非洲和其他国家分离的 dhps 中的单核苷酸多态性（SNP），突出了其区域分布及其与结构的联系。总共对来自 13 个国家的 6336 个基因组序列进行了 SNP、单倍型和基于结构的分析。SNP 分析表明，所有国家的关键 SDX 耐药标记 A437G 几乎固定，在马拉维达到峰值。突变 A613S 除了在刚果民主共和国和马拉维的分离株中很少见。分子对接表明，与野生型蛋白相比，突变蛋白的相互作用普遍丧失。在 MD 模拟过程中，在运行时间结束之前，SDX 从突变体 A581G 和 A613S 的活性部位释放出来，而突变体 A613S 和单倍型 A437A/A581G/A613S 观察到 SDX 与 A613S 的不稳定结合。突变体 A581G 及其单倍型 A581G/A613S、A437G/A581G 和 A437G/A581G/A613S 发生构象变化。旋半径揭示了 A613S、K540E/A581G 和 A437G/A581G 系统的展开行为。总的来说，通过 dhps SNP 的连续分析来跟踪这些突变是值得鼓励的。dhps 结构上的 SNP 可能导致蛋白-药物功能丧失，这可能影响 SDX 在预防孕妇和儿童疟疾中的适用性。
