Pneumococcal Evasion of Antibiotics via Metabolic Adaptation During Infection

Dao, T.; Echlin, H.; McKnight, A.; Marr, E.; Junker, J.; Jia, Q.; Hayden, R.; Rosch, J.

doi:10.1101/2022.04.14.488313

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bioRxiv · 10.1101/2022.04.14.488313

Pneumococcal Evasion of Antibiotics via Metabolic Adaptation During Infection

Dao, T.·Echlin, H.·McKnight, A.·Marr, E.·Junker, J.·Jia, Q.·Hayden, R.·Rosch, J.

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Abstract

Streptococcus pneumoniae is a major human pathogen of global health concern, causing a range of mild to severe infections, including acute otitis media, pneumonia, sepsis, and meningitis. The rapid emergence of antibiotic resistance among S. pneumoniae isolates poses a serious public health problem worldwide. Resistant pneumococcal strains have rendered the mainstay treatment with beta-lactams, fluoroquinolones, and macrolides, ineffective. Antibiotic resistance in S. pneumoniae has spread globally via the emergence of de novo mutations and horizontal transfer of resistance. Fluoroquinolone resistance in S. pneumoniae is an intriguing case because the prevalence of fluoroquinolone resistance does not correlate with increasing usage, as is often the case with other classes of antibiotics. In this study, we demonstrated that deleterious fitness costs constrain the emergence of individual fluoroquinolone resistance mutations in either topoisomerase IV or gyrase A in S. pneumoniae. Generation of double point mutations in the target enzymes in topoisomerase IV and gyrase A conferred high-level fluoroquinolone resistance while restoring fitness comparable to the sensitive wild-type. During an in vivo model of antibiotic resistance evolution, S. pneumoniae was able to circumvent deleterious fitness costs imposed by resistance determinants through development of antibiotic tolerance through metabolic adaptation that reduced the production of reactive oxygen species, an effect that could be recapitulated pharmacologically. The metabolic mutants conferring tolerance resulted in a fitness benefit during infection following antibiotic treatment with fluroquinolones. These data suggest that emergence of fluoroquinolone resistance is tightly constrained in S. pneumoniae by host fitness tradeoffs and that mutational pathways involving metabolic networks to enable tolerance phenotypes may be an important contributor to the evasion of antibiotic mediated killing.

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Dao, T., Echlin, H., McKnight, A., Marr, E., Junker, J., Jia, Q., Hayden, R., Rosch, J.. 2022-04-15. Pneumococcal Evasion of Antibiotics via Metabolic Adaptation During Infection. https://doi.org/10.1101/2022.04.14.488313

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