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Proc Natl Acad Sci U S A ; 120(41): e2308029120, 2023 10 10.
Artigo em Inglês | MEDLINE | ID: mdl-37796984

RESUMO

Streptococcus pneumoniae is a major human pathogen and rising resistance to ß-lactam antibiotics, such as penicillin, is a significant threat to global public health. Mutations occurring in the penicillin-binding proteins (PBPs) can confer high-level penicillin resistance but other poorly understood genetic factors are also important. Here, we combined strictly controlled laboratory experiments and population analyses to identify a new penicillin resistance pathway that is independent of PBP modification. Initial laboratory selection experiments identified high-frequency pde1 mutations conferring S. pneumoniae penicillin resistance. The importance of variation at the pde1 locus was confirmed in natural and clinical populations in an analysis of >7,200 S. pneumoniae genomes. The pde1 mutations identified by these approaches reduce the hydrolytic activity of the Pde1 enzyme in bacterial cells and thereby elevate levels of cyclic-di-adenosine monophosphate and penicillin resistance. Our results reveal rapid de novo loss of function mutations in pde1 as an evolutionary gateway conferring low-level penicillin resistance. This relatively simple genomic change allows cells to persist in populations on an adaptive evolutionary pathway to acquire further genetic changes and high-level penicillin resistance.


Assuntos
Streptococcus pneumoniae , Resistência beta-Lactâmica , Humanos , Resistência beta-Lactâmica/genética , Proteínas de Ligação às Penicilinas/metabolismo , Resistência às Penicilinas/genética , Penicilinas/farmacologia , Penicilinas/metabolismo , Proteínas de Bactérias/metabolismo , Antibacterianos/farmacologia , Testes de Sensibilidade Microbiana
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