Development of antibacterial compounds that constrain evolutionary pathways to resistance
Antibiotic resistance is a worldwide challenge. A potential approach to block resistance is to simultaneously inhibit WT and known escape variants of the target bacterial protein. Here, we applied an integrated computational and experimental approach to discover compounds that inhibit both WT and tr...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
| Published: |
eLife Sciences Publications Ltd
2021-07-01
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| Series: | eLife |
| Subjects: | |
| Online Access: | https://elifesciences.org/articles/64518 |
| _version_ | 1797998446909587456 |
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| author | Yanmin Zhang Sourav Chowdhury João V Rodrigues Eugene Shakhnovich |
| author_facet | Yanmin Zhang Sourav Chowdhury João V Rodrigues Eugene Shakhnovich |
| author_sort | Yanmin Zhang |
| collection | DOAJ |
| description | Antibiotic resistance is a worldwide challenge. A potential approach to block resistance is to simultaneously inhibit WT and known escape variants of the target bacterial protein. Here, we applied an integrated computational and experimental approach to discover compounds that inhibit both WT and trimethoprim (TMP) resistant mutants of E. coli dihydrofolate reductase (DHFR). We identified a novel compound (CD15-3) that inhibits WT DHFR and its TMP resistant variants L28R, P21L and A26T with IC50 50–75 µM against WT and TMP-resistant strains. Resistance to CD15-3 was dramatically delayed compared to TMP in in vitro evolution. Whole genome sequencing of CD15-3-resistant strains showed no mutations in the target folA locus. Rather, gene duplication of several efflux pumps gave rise to weak (about twofold increase in IC50) resistance against CD15-3. Altogether, our results demonstrate the promise of strategy to develop evolution drugs - compounds which constrain evolutionary escape routes in pathogens. |
| first_indexed | 2024-04-11T10:48:54Z |
| format | Article |
| id | doaj.art-7a642803bf564a9caf6ec50bfa00229a |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-11T10:48:54Z |
| publishDate | 2021-07-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-7a642803bf564a9caf6ec50bfa00229a2022-12-22T04:28:58ZengeLife Sciences Publications LtdeLife2050-084X2021-07-011010.7554/eLife.64518Development of antibacterial compounds that constrain evolutionary pathways to resistanceYanmin Zhang0https://orcid.org/0000-0002-4075-7556Sourav Chowdhury1https://orcid.org/0000-0002-1148-2995João V Rodrigues2https://orcid.org/0000-0002-5605-656XEugene Shakhnovich3https://orcid.org/0000-0002-4769-2265School of Science, China Pharmaceutical University, Nanjing, China; Department of Chemistry and Chemical Biology, Harvard University, Cambridge, United StatesDepartment of Chemistry and Chemical Biology, Harvard University, Cambridge, United StatesDepartment of Chemistry and Chemical Biology, Harvard University, Cambridge, United StatesDepartment of Chemistry and Chemical Biology, Harvard University, Cambridge, United StatesAntibiotic resistance is a worldwide challenge. A potential approach to block resistance is to simultaneously inhibit WT and known escape variants of the target bacterial protein. Here, we applied an integrated computational and experimental approach to discover compounds that inhibit both WT and trimethoprim (TMP) resistant mutants of E. coli dihydrofolate reductase (DHFR). We identified a novel compound (CD15-3) that inhibits WT DHFR and its TMP resistant variants L28R, P21L and A26T with IC50 50–75 µM against WT and TMP-resistant strains. Resistance to CD15-3 was dramatically delayed compared to TMP in in vitro evolution. Whole genome sequencing of CD15-3-resistant strains showed no mutations in the target folA locus. Rather, gene duplication of several efflux pumps gave rise to weak (about twofold increase in IC50) resistance against CD15-3. Altogether, our results demonstrate the promise of strategy to develop evolution drugs - compounds which constrain evolutionary escape routes in pathogens.https://elifesciences.org/articles/64518antibiotic resistanceevolution drugcomputational modellingdihydrofolate reductase |
| spellingShingle | Yanmin Zhang Sourav Chowdhury João V Rodrigues Eugene Shakhnovich Development of antibacterial compounds that constrain evolutionary pathways to resistance eLife antibiotic resistance evolution drug computational modelling dihydrofolate reductase |
| title | Development of antibacterial compounds that constrain evolutionary pathways to resistance |
| title_full | Development of antibacterial compounds that constrain evolutionary pathways to resistance |
| title_fullStr | Development of antibacterial compounds that constrain evolutionary pathways to resistance |
| title_full_unstemmed | Development of antibacterial compounds that constrain evolutionary pathways to resistance |
| title_short | Development of antibacterial compounds that constrain evolutionary pathways to resistance |
| title_sort | development of antibacterial compounds that constrain evolutionary pathways to resistance |
| topic | antibiotic resistance evolution drug computational modelling dihydrofolate reductase |
| url | https://elifesciences.org/articles/64518 |
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