Streptococcus pneumoniae favors tolerance via metabolic adaptation over resistance to circumvent fluoroquinolones
ABSTRACT Streptococcus pneumoniae is a major human pathogen of global health concern and the rapid emergence of antibiotic resistance poses a serious public health problem worldwide. Fluoroquinolone resistance in S. pneumoniae is an intriguing case because the prevalence of fluoroquinolone resistanc...
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| Format: | Article |
| Language: | English |
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American Society for Microbiology
2024-02-01
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| Series: | mBio |
| Subjects: | |
| Online Access: | https://journals.asm.org/doi/10.1128/mbio.02828-23 |
| _version_ | 1827150281492660224 |
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| author | Tina H. Dao Haley Echlin Abigail McKnight Enolia S. Marr Julia Junker Qidong Jia Randall Hayden Tim van Opijnen Ralph R. Isberg Vaughn S. Cooper Jason W. Rosch |
| author_facet | Tina H. Dao Haley Echlin Abigail McKnight Enolia S. Marr Julia Junker Qidong Jia Randall Hayden Tim van Opijnen Ralph R. Isberg Vaughn S. Cooper Jason W. Rosch |
| author_sort | Tina H. Dao |
| collection | DOAJ |
| description | ABSTRACT Streptococcus pneumoniae is a major human pathogen of global health concern and the rapid emergence of antibiotic resistance poses a serious public health problem worldwide. Fluoroquinolone resistance in S. pneumoniae is an intriguing case because the prevalence of fluoroquinolone resistance does not correlate with increasing usage and has remained rare. Our data indicate that deleterious fitness costs in the mammalian host constrain the emergence of fluoroquinolone resistance both by de novo mutation and recombination. S. pneumoniae was able to circumvent such deleterious fitness costs via the development of antibiotic tolerance through metabolic adaptation that reduced the production of reactive oxygen species, resulting in a fitness benefit during infection of mice treated with fluoroquinolones. These data suggest that the emergence of fluoroquinolone resistance is tightly constrained in S. pneumoniae by fitness tradeoffs and that mutational pathways involving metabolic networks to enable tolerance phenotypes are an important contributor to the evasion of antibiotic-mediated killing.IMPORTANCEThe increasing prevalence of antibiotic resistant bacteria is a major global health concern. While many species have the potential to develop antibiotic resistance, understanding the barriers to resistance emergence in the clinic remains poorly understood. A prime example of this is fluroquinolone resistance in Streptococcus pneumoniae, whereby, despite continued utilization, resistance to this class of antibiotic remains rare. In this study, we found that the predominant pathways for developing resistance to this antibiotic class severely compromised the infectious capacity of the pneumococcus, providing a key impediment for the emergence of resistance. Using in vivo models of experimental evolution, we found that S. pneumoniae responds to repeated fluoroquinolone exposure by modulating key metabolic pathways involved in the generation of redox molecules, which leads to antibiotic treatment failure in the absence of appreciable shifts in resistance levels. These data underscore the complex pathways available to pathogens to evade antibiotic mediating killing via antibiotic tolerance. |
| first_indexed | 2024-03-08T01:25:31Z |
| format | Article |
| id | doaj.art-10335ee40e3a4874ba67dd41ae6ffedc |
| institution | Directory Open Access Journal |
| issn | 2150-7511 |
| language | English |
| last_indexed | 2025-03-20T21:31:35Z |
| publishDate | 2024-02-01 |
| publisher | American Society for Microbiology |
| record_format | Article |
| series | mBio |
| spelling | doaj.art-10335ee40e3a4874ba67dd41ae6ffedc2024-08-11T18:24:59ZengAmerican Society for MicrobiologymBio2150-75112024-02-0115210.1128/mbio.02828-23Streptococcus pneumoniae favors tolerance via metabolic adaptation over resistance to circumvent fluoroquinolonesTina H. Dao0Haley Echlin1Abigail McKnight2Enolia S. Marr3Julia Junker4Qidong Jia5Randall Hayden6Tim van Opijnen7Ralph R. Isberg8Vaughn S. Cooper9Jason W. Rosch10Department of Infectious Diseases, St. Jude Children’s Research Hospital, Memphis, Tennessee, USADepartment of Infectious Diseases, St. Jude Children’s Research Hospital, Memphis, Tennessee, USADepartment of Infectious Diseases, St. Jude Children’s Research Hospital, Memphis, Tennessee, USADepartment of Infectious Diseases, St. Jude Children’s Research Hospital, Memphis, Tennessee, USANationales Referenzzentrum für Streptokokken Abteilung Medizinische Mikrobiologie, Universitätsklinikum RWTH Aachen, Aachen, GermanyDepartment of Infectious Diseases, St. Jude Children’s Research Hospital, Memphis, Tennessee, USADepartment of Pathology, St. Jude Children’s Research Hospital, Memphis, Tennessee, USABroad Institute of MIT and Harvard, Cambridge, Massachusetts, USADeptartment of Molecular Biology and Microbiology, Tufts University School of Medicine, Boston, Massachusetts, USACenter for Evolutionary Biology and Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USADepartment of Infectious Diseases, St. Jude Children’s Research Hospital, Memphis, Tennessee, USAABSTRACT Streptococcus pneumoniae is a major human pathogen of global health concern and the rapid emergence of antibiotic resistance poses a serious public health problem worldwide. Fluoroquinolone resistance in S. pneumoniae is an intriguing case because the prevalence of fluoroquinolone resistance does not correlate with increasing usage and has remained rare. Our data indicate that deleterious fitness costs in the mammalian host constrain the emergence of fluoroquinolone resistance both by de novo mutation and recombination. S. pneumoniae was able to circumvent such deleterious fitness costs via the development of antibiotic tolerance through metabolic adaptation that reduced the production of reactive oxygen species, resulting in a fitness benefit during infection of mice treated with fluoroquinolones. These data suggest that the emergence of fluoroquinolone resistance is tightly constrained in S. pneumoniae by fitness tradeoffs and that mutational pathways involving metabolic networks to enable tolerance phenotypes are an important contributor to the evasion of antibiotic-mediated killing.IMPORTANCEThe increasing prevalence of antibiotic resistant bacteria is a major global health concern. While many species have the potential to develop antibiotic resistance, understanding the barriers to resistance emergence in the clinic remains poorly understood. A prime example of this is fluroquinolone resistance in Streptococcus pneumoniae, whereby, despite continued utilization, resistance to this class of antibiotic remains rare. In this study, we found that the predominant pathways for developing resistance to this antibiotic class severely compromised the infectious capacity of the pneumococcus, providing a key impediment for the emergence of resistance. Using in vivo models of experimental evolution, we found that S. pneumoniae responds to repeated fluoroquinolone exposure by modulating key metabolic pathways involved in the generation of redox molecules, which leads to antibiotic treatment failure in the absence of appreciable shifts in resistance levels. These data underscore the complex pathways available to pathogens to evade antibiotic mediating killing via antibiotic tolerance.https://journals.asm.org/doi/10.1128/mbio.02828-23Streptococcus pneumoniaeantibiotic resistancevirulence |
| spellingShingle | Tina H. Dao Haley Echlin Abigail McKnight Enolia S. Marr Julia Junker Qidong Jia Randall Hayden Tim van Opijnen Ralph R. Isberg Vaughn S. Cooper Jason W. Rosch Streptococcus pneumoniae favors tolerance via metabolic adaptation over resistance to circumvent fluoroquinolones mBio Streptococcus pneumoniae antibiotic resistance virulence |
| title | Streptococcus pneumoniae favors tolerance via metabolic adaptation over resistance to circumvent fluoroquinolones |
| title_full | Streptococcus pneumoniae favors tolerance via metabolic adaptation over resistance to circumvent fluoroquinolones |
| title_fullStr | Streptococcus pneumoniae favors tolerance via metabolic adaptation over resistance to circumvent fluoroquinolones |
| title_full_unstemmed | Streptococcus pneumoniae favors tolerance via metabolic adaptation over resistance to circumvent fluoroquinolones |
| title_short | Streptococcus pneumoniae favors tolerance via metabolic adaptation over resistance to circumvent fluoroquinolones |
| title_sort | streptococcus pneumoniae favors tolerance via metabolic adaptation over resistance to circumvent fluoroquinolones |
| topic | Streptococcus pneumoniae antibiotic resistance virulence |
| url | https://journals.asm.org/doi/10.1128/mbio.02828-23 |
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