Efflux pump gene amplifications bypass necessity of multiple target mutations for resistance against dual-targeting antibiotic
Abstract Antibiotics that have multiple cellular targets theoretically reduce the frequency of resistance evolution, but adaptive trajectories and resistance mechanisms against such antibiotics are understudied. Here we investigate these in methicillin resistant Staphylococcus aureus (MRSA) using ex...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-06-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-38507-4 |
| _version_ | 1797806657647935488 |
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| author | Kalinga Pavan T. Silva Ganesh Sundar Anupama Khare |
| author_facet | Kalinga Pavan T. Silva Ganesh Sundar Anupama Khare |
| author_sort | Kalinga Pavan T. Silva |
| collection | DOAJ |
| description | Abstract Antibiotics that have multiple cellular targets theoretically reduce the frequency of resistance evolution, but adaptive trajectories and resistance mechanisms against such antibiotics are understudied. Here we investigate these in methicillin resistant Staphylococcus aureus (MRSA) using experimental evolution upon exposure to delafloxacin (DLX), a novel fluoroquinolone that targets both DNA gyrase and topoisomerase IV. We show that selection for coding sequence mutations and genomic amplifications of the gene encoding a poorly characterized efflux pump, SdrM, leads to high DLX resistance, circumventing the requirement for mutations in both target enzymes. In the evolved populations, sdrM overexpression due to genomic amplifications containing sdrM and two adjacent genes encoding efflux pumps results in high DLX resistance, while the adjacent hitchhiking efflux pumps contribute to streptomycin cross-resistance. Further, lack of sdrM necessitates mutations in both target enzymes to evolve DLX resistance, and sdrM thus increases the frequency of resistance evolution. Finally, sdrM mutations and amplifications are similarly selected in two diverse clinical isolates, indicating the generality of this DLX resistance mechanism. Our study highlights that instead of reduced rates of resistance, evolution of resistance to multi-targeting antibiotics can involve alternate high-frequency evolutionary paths, that may cause unexpected alterations of the fitness landscape, including antibiotic cross-resistance. |
| first_indexed | 2024-03-13T06:10:37Z |
| format | Article |
| id | doaj.art-950b6bc9c2374e618df83bd5a10d9a1a |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-13T06:10:37Z |
| publishDate | 2023-06-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-950b6bc9c2374e618df83bd5a10d9a1a2023-06-11T11:18:22ZengNature PortfolioNature Communications2041-17232023-06-0114111410.1038/s41467-023-38507-4Efflux pump gene amplifications bypass necessity of multiple target mutations for resistance against dual-targeting antibioticKalinga Pavan T. Silva0Ganesh Sundar1Anupama Khare2Laboratory of Molecular Biology, National Cancer Institute, National Institutes of HealthLaboratory of Molecular Biology, National Cancer Institute, National Institutes of HealthLaboratory of Molecular Biology, National Cancer Institute, National Institutes of HealthAbstract Antibiotics that have multiple cellular targets theoretically reduce the frequency of resistance evolution, but adaptive trajectories and resistance mechanisms against such antibiotics are understudied. Here we investigate these in methicillin resistant Staphylococcus aureus (MRSA) using experimental evolution upon exposure to delafloxacin (DLX), a novel fluoroquinolone that targets both DNA gyrase and topoisomerase IV. We show that selection for coding sequence mutations and genomic amplifications of the gene encoding a poorly characterized efflux pump, SdrM, leads to high DLX resistance, circumventing the requirement for mutations in both target enzymes. In the evolved populations, sdrM overexpression due to genomic amplifications containing sdrM and two adjacent genes encoding efflux pumps results in high DLX resistance, while the adjacent hitchhiking efflux pumps contribute to streptomycin cross-resistance. Further, lack of sdrM necessitates mutations in both target enzymes to evolve DLX resistance, and sdrM thus increases the frequency of resistance evolution. Finally, sdrM mutations and amplifications are similarly selected in two diverse clinical isolates, indicating the generality of this DLX resistance mechanism. Our study highlights that instead of reduced rates of resistance, evolution of resistance to multi-targeting antibiotics can involve alternate high-frequency evolutionary paths, that may cause unexpected alterations of the fitness landscape, including antibiotic cross-resistance.https://doi.org/10.1038/s41467-023-38507-4 |
| spellingShingle | Kalinga Pavan T. Silva Ganesh Sundar Anupama Khare Efflux pump gene amplifications bypass necessity of multiple target mutations for resistance against dual-targeting antibiotic Nature Communications |
| title | Efflux pump gene amplifications bypass necessity of multiple target mutations for resistance against dual-targeting antibiotic |
| title_full | Efflux pump gene amplifications bypass necessity of multiple target mutations for resistance against dual-targeting antibiotic |
| title_fullStr | Efflux pump gene amplifications bypass necessity of multiple target mutations for resistance against dual-targeting antibiotic |
| title_full_unstemmed | Efflux pump gene amplifications bypass necessity of multiple target mutations for resistance against dual-targeting antibiotic |
| title_short | Efflux pump gene amplifications bypass necessity of multiple target mutations for resistance against dual-targeting antibiotic |
| title_sort | efflux pump gene amplifications bypass necessity of multiple target mutations for resistance against dual targeting antibiotic |
| url | https://doi.org/10.1038/s41467-023-38507-4 |
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