The penicillin binding protein 1A of Helicobacter pylori, its amoxicillin binding site and access routes
| Autor: | Najmeh Salehi, Mahmoud Eshagh Hosseini, Bahareh Ghadiri, Bahareh Attaran, Mohammad Tashakoripour, Shadi Kalateh, Maryam Esmaeili, Marjan Mohammadi |
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| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Thr556Ser RC799-869 medicine.disease_cause Microbiology Binding site PBP1A 03 medical and health sciences Residue (chemistry) 0302 clinical medicine Virology Streptococcus pneumoniae medicine S414R Gene chemistry.chemical_classification V469M biology Chemistry Research Gastroenterology Amoxicillin Diseases of the digestive system. Gastroenterology Helicobacter pylori biology.organism_classification Resistant Molecular biology Amino acid 030104 developmental biology Infectious Diseases Docking (molecular) Drug Binding Site Access tunnel 030211 gastroenterology & hepatology Parasitology H. pylori |
| Zdroj: | Gut Pathogens, Vol 13, Iss 1, Pp 1-8 (2021) Gut Pathogens |
| ISSN: | 1757-4749 |
| Popis: | Background 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. Results 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. Conclusions 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. |
| Databáze: | OpenAIRE |
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