D-Mannoside FimH Inhibitors as Non-Antibiotic Alternatives for Uropathogenic <i>Escherichia coli</i>
FimH is a type I fimbria of uropathogenic <i>Escherichia coli</i> (UPEC), recognized for its ability to adhere and infect epithelial urinary tissue. Due to its role in the virulence of UPEC, several therapeutic strategies have focused on the study of FimH, including vaccines, mannosides,...
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MDPI AG
2021-09-01
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| Series: | Antibiotics |
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| Online Access: | https://www.mdpi.com/2079-6382/10/9/1072 |
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| author | Alfredo Montes-Robledo Rosa Baldiris-Avila Johan Fabian Galindo |
| author_facet | Alfredo Montes-Robledo Rosa Baldiris-Avila Johan Fabian Galindo |
| author_sort | Alfredo Montes-Robledo |
| collection | DOAJ |
| description | FimH is a type I fimbria of uropathogenic <i>Escherichia coli</i> (UPEC), recognized for its ability to adhere and infect epithelial urinary tissue. Due to its role in the virulence of UPEC, several therapeutic strategies have focused on the study of FimH, including vaccines, mannosides, and molecules that inhibit their assembly. This work has focused on the ability of a set of monosubstituted and disubstituted phenyl mannosides to inhibit FimH. To determine the 3D structure of FimH for our in silico studies, we obtained fifteen sequences by PCR amplification of the <i>fimH</i> gene from 102 UPEC isolates. The <i>fimH</i> sequences in BLAST had a high homology (97–100%) to our UPEC <i>fimH</i> sequences. A search for the three-dimensional crystallographic structure of FimH proteins in the PDB server showed that proteins 4X5P and 4XO9 were found in 10 of the 15 isolates, presenting a 67% influx among our UPEC isolates. We focused on these two proteins to study the stability, free energy, and the interactions with different mannoside ligands. We found that the interactions with the residues of aspartic acid (ASP 54) and glutamine (GLN 133) were significant to the binding stability. The ligands assessed demonstrated high binding affinity and stability with the lectin domain of FimH proteins during the molecular dynamic simulations, based on MM-PBSA analysis. Therefore, our results suggest the potential utility of phenyl mannoside derivatives as FimH inhibitors to mitigate urinary tract infections produced by UPEC; thus, decreasing colonization, disease burden, and the costs of medical care. |
| first_indexed | 2024-03-10T07:57:08Z |
| format | Article |
| id | doaj.art-7b1e024519f042d193d6a75d975c0fef |
| institution | Directory Open Access Journal |
| issn | 2079-6382 |
| language | English |
| last_indexed | 2024-03-10T07:57:08Z |
| publishDate | 2021-09-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Antibiotics |
| spelling | doaj.art-7b1e024519f042d193d6a75d975c0fef2023-11-22T11:45:49ZengMDPI AGAntibiotics2079-63822021-09-01109107210.3390/antibiotics10091072D-Mannoside FimH Inhibitors as Non-Antibiotic Alternatives for Uropathogenic <i>Escherichia coli</i>Alfredo Montes-Robledo0Rosa Baldiris-Avila1Johan Fabian Galindo2Grupo de Investigación Microbiología Clínica y Ambiental, Facultad de Ciencias Exactas y Naturales, Universidad de Cartagena, Cartagena de Indias 13001, ColombiaGrupo de Investigación Microbiología Clínica y Ambiental, Facultad de Ciencias Exactas y Naturales, Universidad de Cartagena, Cartagena de Indias 13001, ColombiaDepartamento de Química, Universidad Nacional de Colombia, Bogotá 11321, ColombiaFimH is a type I fimbria of uropathogenic <i>Escherichia coli</i> (UPEC), recognized for its ability to adhere and infect epithelial urinary tissue. Due to its role in the virulence of UPEC, several therapeutic strategies have focused on the study of FimH, including vaccines, mannosides, and molecules that inhibit their assembly. This work has focused on the ability of a set of monosubstituted and disubstituted phenyl mannosides to inhibit FimH. To determine the 3D structure of FimH for our in silico studies, we obtained fifteen sequences by PCR amplification of the <i>fimH</i> gene from 102 UPEC isolates. The <i>fimH</i> sequences in BLAST had a high homology (97–100%) to our UPEC <i>fimH</i> sequences. A search for the three-dimensional crystallographic structure of FimH proteins in the PDB server showed that proteins 4X5P and 4XO9 were found in 10 of the 15 isolates, presenting a 67% influx among our UPEC isolates. We focused on these two proteins to study the stability, free energy, and the interactions with different mannoside ligands. We found that the interactions with the residues of aspartic acid (ASP 54) and glutamine (GLN 133) were significant to the binding stability. The ligands assessed demonstrated high binding affinity and stability with the lectin domain of FimH proteins during the molecular dynamic simulations, based on MM-PBSA analysis. Therefore, our results suggest the potential utility of phenyl mannoside derivatives as FimH inhibitors to mitigate urinary tract infections produced by UPEC; thus, decreasing colonization, disease burden, and the costs of medical care.https://www.mdpi.com/2079-6382/10/9/1072UPECFimHmolecular dynamicsvirulence factorsantibiotic resistance |
| spellingShingle | Alfredo Montes-Robledo Rosa Baldiris-Avila Johan Fabian Galindo D-Mannoside FimH Inhibitors as Non-Antibiotic Alternatives for Uropathogenic <i>Escherichia coli</i> Antibiotics UPEC FimH molecular dynamics virulence factors antibiotic resistance |
| title | D-Mannoside FimH Inhibitors as Non-Antibiotic Alternatives for Uropathogenic <i>Escherichia coli</i> |
| title_full | D-Mannoside FimH Inhibitors as Non-Antibiotic Alternatives for Uropathogenic <i>Escherichia coli</i> |
| title_fullStr | D-Mannoside FimH Inhibitors as Non-Antibiotic Alternatives for Uropathogenic <i>Escherichia coli</i> |
| title_full_unstemmed | D-Mannoside FimH Inhibitors as Non-Antibiotic Alternatives for Uropathogenic <i>Escherichia coli</i> |
| title_short | D-Mannoside FimH Inhibitors as Non-Antibiotic Alternatives for Uropathogenic <i>Escherichia coli</i> |
| title_sort | d mannoside fimh inhibitors as non antibiotic alternatives for uropathogenic i escherichia coli i |
| topic | UPEC FimH molecular dynamics virulence factors antibiotic resistance |
| url | https://www.mdpi.com/2079-6382/10/9/1072 |
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