Mutational signature analysis predicts bacterial hypermutation and multidrug resistance
Abstract Bacteria of clinical importance, such as Pseudomonas aeruginosa, can become hypermutators upon loss of DNA mismatch repair (MMR) and are clinically correlated with high rates of multidrug resistance (MDR). Here, we demonstrate that hypermutated MMR-deficient P. aeruginosa has a unique mutat...
Saved in:
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2025-01-01
|
| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-55206-w |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1841559310515044352 |
|---|---|
| author | Kalen M. Hall Leonard G. Williams Richard D. Smith Erin A. Kuang Robert K. Ernst Christine M. Bojanowski William C. Wimley Lisa A. Morici Zachary F. Pursell |
| author_facet | Kalen M. Hall Leonard G. Williams Richard D. Smith Erin A. Kuang Robert K. Ernst Christine M. Bojanowski William C. Wimley Lisa A. Morici Zachary F. Pursell |
| author_sort | Kalen M. Hall |
| collection | DOAJ |
| description | Abstract Bacteria of clinical importance, such as Pseudomonas aeruginosa, can become hypermutators upon loss of DNA mismatch repair (MMR) and are clinically correlated with high rates of multidrug resistance (MDR). Here, we demonstrate that hypermutated MMR-deficient P. aeruginosa has a unique mutational signature and rapidly acquires MDR upon repeated exposure to first-line or last-resort antibiotics. MDR acquisition was irrespective of drug class and instead arose through common resistance mechanisms shared between the initial and secondary drugs. Rational combinations of drugs having distinct resistance mechanisms prevented MDR acquisition in hypermutated MMR-deficient P. aeruginosa. Mutational signature analysis of P. aeruginosa across different human disease contexts identified appreciable quantities of MMR-deficient clinical isolates that were already MDR or prone to future MDR acquisition. Mutational signature analysis of patient samples is a promising diagnostic tool that may predict MDR and guide precision-based medical care. |
| format | Article |
| id | doaj-art-b5195bdbd0fb417aa0b5e56d48040b16 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-b5195bdbd0fb417aa0b5e56d48040b162025-01-05T12:38:36ZengNature PortfolioNature Communications2041-17232025-01-0116111610.1038/s41467-024-55206-wMutational signature analysis predicts bacterial hypermutation and multidrug resistanceKalen M. Hall0Leonard G. Williams1Richard D. Smith2Erin A. Kuang3Robert K. Ernst4Christine M. Bojanowski5William C. Wimley6Lisa A. Morici7Zachary F. Pursell8Department of Microbiology and Immunology, School of Medicine, Tulane UniversityDepartment of Biochemistry and Molecular Biology, School of Medicine, Tulane UniversityDepartment of Microbial Pathogenesis, School of Dentistry, University of MarylandDepartment of Microbiology and Immunology, School of Medicine, Tulane UniversityDepartment of Microbial Pathogenesis, School of Dentistry, University of MarylandDepartment of Medicine, School of Medicine, Tulane UniversityDepartment of Biochemistry and Molecular Biology, School of Medicine, Tulane UniversityDepartment of Microbiology and Immunology, School of Medicine, Tulane UniversityDepartment of Biochemistry and Molecular Biology, School of Medicine, Tulane UniversityAbstract Bacteria of clinical importance, such as Pseudomonas aeruginosa, can become hypermutators upon loss of DNA mismatch repair (MMR) and are clinically correlated with high rates of multidrug resistance (MDR). Here, we demonstrate that hypermutated MMR-deficient P. aeruginosa has a unique mutational signature and rapidly acquires MDR upon repeated exposure to first-line or last-resort antibiotics. MDR acquisition was irrespective of drug class and instead arose through common resistance mechanisms shared between the initial and secondary drugs. Rational combinations of drugs having distinct resistance mechanisms prevented MDR acquisition in hypermutated MMR-deficient P. aeruginosa. Mutational signature analysis of P. aeruginosa across different human disease contexts identified appreciable quantities of MMR-deficient clinical isolates that were already MDR or prone to future MDR acquisition. Mutational signature analysis of patient samples is a promising diagnostic tool that may predict MDR and guide precision-based medical care.https://doi.org/10.1038/s41467-024-55206-w |
| spellingShingle | Kalen M. Hall Leonard G. Williams Richard D. Smith Erin A. Kuang Robert K. Ernst Christine M. Bojanowski William C. Wimley Lisa A. Morici Zachary F. Pursell Mutational signature analysis predicts bacterial hypermutation and multidrug resistance Nature Communications |
| title | Mutational signature analysis predicts bacterial hypermutation and multidrug resistance |
| title_full | Mutational signature analysis predicts bacterial hypermutation and multidrug resistance |
| title_fullStr | Mutational signature analysis predicts bacterial hypermutation and multidrug resistance |
| title_full_unstemmed | Mutational signature analysis predicts bacterial hypermutation and multidrug resistance |
| title_short | Mutational signature analysis predicts bacterial hypermutation and multidrug resistance |
| title_sort | mutational signature analysis predicts bacterial hypermutation and multidrug resistance |
| url | https://doi.org/10.1038/s41467-024-55206-w |
| work_keys_str_mv | AT kalenmhall mutationalsignatureanalysispredictsbacterialhypermutationandmultidrugresistance AT leonardgwilliams mutationalsignatureanalysispredictsbacterialhypermutationandmultidrugresistance AT richarddsmith mutationalsignatureanalysispredictsbacterialhypermutationandmultidrugresistance AT erinakuang mutationalsignatureanalysispredictsbacterialhypermutationandmultidrugresistance AT robertkernst mutationalsignatureanalysispredictsbacterialhypermutationandmultidrugresistance AT christinembojanowski mutationalsignatureanalysispredictsbacterialhypermutationandmultidrugresistance AT williamcwimley mutationalsignatureanalysispredictsbacterialhypermutationandmultidrugresistance AT lisaamorici mutationalsignatureanalysispredictsbacterialhypermutationandmultidrugresistance AT zacharyfpursell mutationalsignatureanalysispredictsbacterialhypermutationandmultidrugresistance |