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The penicillin binding protein 1A of Helicobacter pylori, its amoxicillin binding site and access routes
Gut Pathogens ( IF 4.3 ) Pub Date : 2021-06-28 , DOI: 10.1186/s13099-021-00438-0
Bahareh Attaran 1, 2 , Najmeh Salehi 3 , Bahareh Ghadiri 1 , Maryam Esmaeili 1 , Shadi Kalateh 1 , Mohammad Tashakoripour 4 , Mahmoud Eshagh Hosseini 4 , Marjan Mohammadi 1
Affiliation  

Amoxicillin-resistant H. pylori strains are increasing worldwide. To explore the potential resistance mechanisms involved, the 3D structure modeling and access tunnel prediction for penicillin-binding proteins (PBP1A) was performed, based on the Streptococcus pneumoniae, PBP 3D structure. Molecular covalent docking was used to determine the interactions between amoxicillin (AMX) and PBP1A. The AMX-Ser368 covalent complex interacts with the binding site residues (Gly367, Ala369, ILE370, Lys371, Tyr416, Ser433, Thr541, Thr556, Gly557, Thr558, and Asn560) of PBP1A, non-covalently. Six tunnel-like structures, accessing the PBP1A binding site, were characterized, using the CAVER algorithm. Tunnel-1 was the ultimate access route, leading to the drug catalytic binding residue (Ser368). This tunnel comprises of eighteen amino acid residues, 8 of which are shared with the drug binding site. Subsequently, to screen the presence of PBP1A mutations, in the binding site and tunnel residues, in our clinical strains, in vitro assays were performed. H. pylori strains, isolated under gastroscopy, underwent AMX susceptibility testing by E-test. Of the 100 clinical strains tested, 4 were AMX-resistant. The transpeptidase domain of the pbp1a gene of these resistant, plus 10 randomly selected AMX-susceptible strains, were amplified and sequenced. Of the amino acids lining the tunnel-1 and binding site residues, three (Ser414Arg, Val469Met and Thr556Ser) substitutions, were detected in 2 of the 4 resistant and none of the sequenced susceptible strains, respectively. We hypothesize that mutations in amino acid residues lining the binding site and/or tunnel-1, resulting in conformational/spatial changes, may block drug binding to PBP1A and cause AMX resistance.

中文翻译:

幽门螺杆菌青霉素结合蛋白1A 、阿莫西林结合位点及通路

阿莫西林抗性幽门螺杆菌菌株在世界范围内不断增加。为了探索所涉及的潜在耐药机制,基于肺炎链球菌 PBP 3D 结构,对青霉素结合蛋白 (PBP1A) 进行了 3D 结构建模和通道隧道预测。分子共价对接用于确定阿莫西林 (AMX) 和 PBP1A 之间的相互作用。AMX-Ser368 共价复合物与非共价 PBP1A 的结合位点残基(Gly367、Ala369、ILE370、Lys371、Tyr416、Ser433、Thr541、Thr556、Gly557、Thr558 和 Asn560)相互作用。使用 CAVER 算法表征了访问 PBP1A 结合位点的六个隧道状结构。Tunnel-1 是最终通路,通向药物催化结合残基 (Ser368)。这个隧道由十八个氨基酸残基组成,其中8个与药物结合位点共享。随后,为了在我们的临床菌株中筛选结合位点和隧道残基中 PBP1A 突变的存在,进行了体外测定。在胃镜下分离的幽门螺杆菌菌株通过 E-test 进行 AMX 敏感性测试。在测试的 100 种临床菌株中,4 种具有 AMX 抗性。这些抗性的 pbp1a 基因的转肽酶结构域,加上 10 个随机选择的 AMX 易感菌株,被扩增和测序。在隧道 1 和结合位点残基上的氨基酸中,三个(Ser414Arg、Val469Met 和 Thr556Ser)取代分别在 4 种抗性菌株中的 2 种中检测到,在测序的易感菌株中均未检测到。我们假设结合位点和/或隧道 1 上的氨基酸残基发生突变,
更新日期:2021-06-29
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