Localized pmrB hypermutation drives the evolution of colistin heteroresistance
Colistin has emerged as an important last line of defence for the treatment of infections caused by antibiotic resistant Gram-negative pathogens, but colistin resistance remains poorly understood. Here we investigate the responses of |1,000 populations of an MDR strain of P. aeruginosa to a high dos...
| Main Authors: | , , |
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| Format: | Journal article |
| Language: | English |
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Cell Press
2022
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| _version_ | 1826308220403056640 |
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| author | Kapel, N diaz, J Maclean, R |
| author_facet | Kapel, N diaz, J Maclean, R |
| author_sort | Kapel, N |
| collection | OXFORD |
| description | Colistin has emerged as an important last line of defence for the treatment of infections caused by antibiotic resistant Gram-negative pathogens, but colistin resistance remains poorly understood. Here we investigate the responses of |1,000 populations of an MDR strain of P. aeruginosa to a high dose of colistin. Colistin exposure causes rapid cell death, but some populations eventually recover due to the growth of sub-populations of heteroresistant cells. Heteroresistance is unstable and resistance is rapidly lost under culture in colistin-free medium. The evolution of heteroresistance is primarily driven selection for pre-existing mutations at two hotspot sites in the PmrAB regulatory system. Localized hypermutation of pmrB generates colistin resistance at 103-104 times the background resistance mutation rate(|2x10-5 20 per cell division). PmrAB provides resistance to antimicrobial peptides that are involved in host immunity, suggesting that this pathogen may have evolved a highly mutable pmrB as an adaptation to host immunity. |
| first_indexed | 2024-03-07T07:16:16Z |
| format | Journal article |
| id | oxford-uuid:0f0e8e65-f26f-4f75-9611-297dc00c5544 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T07:16:16Z |
| publishDate | 2022 |
| publisher | Cell Press |
| record_format | dspace |
| spelling | oxford-uuid:0f0e8e65-f26f-4f75-9611-297dc00c55442022-08-23T10:29:19ZLocalized pmrB hypermutation drives the evolution of colistin heteroresistanceJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:0f0e8e65-f26f-4f75-9611-297dc00c5544EnglishSymplectic ElementsCell Press2022Kapel, Ndiaz, JMaclean, RColistin has emerged as an important last line of defence for the treatment of infections caused by antibiotic resistant Gram-negative pathogens, but colistin resistance remains poorly understood. Here we investigate the responses of |1,000 populations of an MDR strain of P. aeruginosa to a high dose of colistin. Colistin exposure causes rapid cell death, but some populations eventually recover due to the growth of sub-populations of heteroresistant cells. Heteroresistance is unstable and resistance is rapidly lost under culture in colistin-free medium. The evolution of heteroresistance is primarily driven selection for pre-existing mutations at two hotspot sites in the PmrAB regulatory system. Localized hypermutation of pmrB generates colistin resistance at 103-104 times the background resistance mutation rate(|2x10-5 20 per cell division). PmrAB provides resistance to antimicrobial peptides that are involved in host immunity, suggesting that this pathogen may have evolved a highly mutable pmrB as an adaptation to host immunity. |
| spellingShingle | Kapel, N diaz, J Maclean, R Localized pmrB hypermutation drives the evolution of colistin heteroresistance |
| title | Localized pmrB hypermutation drives the evolution of colistin heteroresistance |
| title_full | Localized pmrB hypermutation drives the evolution of colistin heteroresistance |
| title_fullStr | Localized pmrB hypermutation drives the evolution of colistin heteroresistance |
| title_full_unstemmed | Localized pmrB hypermutation drives the evolution of colistin heteroresistance |
| title_short | Localized pmrB hypermutation drives the evolution of colistin heteroresistance |
| title_sort | localized pmrb hypermutation drives the evolution of colistin heteroresistance |
| work_keys_str_mv | AT kapeln localizedpmrbhypermutationdrivestheevolutionofcolistinheteroresistance AT diazj localizedpmrbhypermutationdrivestheevolutionofcolistinheteroresistance AT macleanr localizedpmrbhypermutationdrivestheevolutionofcolistinheteroresistance |