Cellular Growth Arrest and Efflux Pumps Are Associated With Antibiotic Persisters in Streptococcus pyogenes Induced in Biofilm-Like Environments
Streptococcus pyogenes (group A Streptococcus-GAS) is an important pathogen for humans. GAS has been associated with severe and invasive diseases. Despite the fact that these bacteria remain universally susceptible to penicillin, therapeutic failures have been reported in some GAS infections. Many h...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2021-09-01
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| Series: | Frontiers in Microbiology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fmicb.2021.716628/full |
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| author | Caroline Lopes Martini Amada Zambrana Coronado Maria Celeste Nunes Melo Clarice Neffa Gobbi Úrsula Santos Lopez Marcos Correa de Mattos Thais Tavares Amorim Ana Maria Nunes Botelho Ana Tereza Ribeiro Vasconcelos Luiz Gonzaga Paula Almeida Paul J. Planet Paul J. Planet Paul J. Planet Russolina Benedeta Zingali Agnes Marie Sá Figueiredo Bernadete Teixeira Ferreira-Carvalho |
| author_facet | Caroline Lopes Martini Amada Zambrana Coronado Maria Celeste Nunes Melo Clarice Neffa Gobbi Úrsula Santos Lopez Marcos Correa de Mattos Thais Tavares Amorim Ana Maria Nunes Botelho Ana Tereza Ribeiro Vasconcelos Luiz Gonzaga Paula Almeida Paul J. Planet Paul J. Planet Paul J. Planet Russolina Benedeta Zingali Agnes Marie Sá Figueiredo Bernadete Teixeira Ferreira-Carvalho |
| author_sort | Caroline Lopes Martini |
| collection | DOAJ |
| description | Streptococcus pyogenes (group A Streptococcus-GAS) is an important pathogen for humans. GAS has been associated with severe and invasive diseases. Despite the fact that these bacteria remain universally susceptible to penicillin, therapeutic failures have been reported in some GAS infections. Many hypotheses have been proposed to explain these antibiotic-unresponsive infections; however, none of them have fully elucidated this phenomenon. In this study, we show that GAS strains have the ability to form antimicrobial persisters when inoculated on abiotic surfaces to form a film of bacterial agglomerates (biofilm-like environment). Our data suggest that efflux pumps were possibly involved in this phenomenon. In fact, gene expression assays by real-time qRT-PCR showed upregulation of some genes associated with efflux pumps in persisters arising in the presence of penicillin. Phenotypic reversion assay and whole-genome sequencing indicated that this event was due to non-inherited resistance mechanisms. The persister cells showed downregulation of genes associated with protein biosynthesis and cell growth, as demonstrated by gene expression assays. Moreover, the proteomic analysis revealed that susceptible cells express higher levels of ribosome proteins. It is remarkable that previous studies have reported the recovery of S. pyogenes viable cells from tissue biopsies of patients presented with GAS invasive infections and submitted to therapy with antibiotics. The persistence phenomenon described herein brings new insights into the origin of therapeutic failures in S. pyogenes infections. Multifactorial mechanisms involving protein synthesis inhibition, cell growth impairment and efflux pumps seem to play roles in the formation of antimicrobial persisters in S. pyogenes. |
| first_indexed | 2024-12-18T00:36:44Z |
| format | Article |
| id | doaj.art-bc2635cab71c46a3bfd499fad03ba97d |
| institution | Directory Open Access Journal |
| issn | 1664-302X |
| language | English |
| last_indexed | 2024-12-18T00:36:44Z |
| publishDate | 2021-09-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Microbiology |
| spelling | doaj.art-bc2635cab71c46a3bfd499fad03ba97d2022-12-21T21:26:59ZengFrontiers Media S.A.Frontiers in Microbiology1664-302X2021-09-011210.3389/fmicb.2021.716628716628Cellular Growth Arrest and Efflux Pumps Are Associated With Antibiotic Persisters in Streptococcus pyogenes Induced in Biofilm-Like EnvironmentsCaroline Lopes Martini0Amada Zambrana Coronado1Maria Celeste Nunes Melo2Clarice Neffa Gobbi3Úrsula Santos Lopez4Marcos Correa de Mattos5Thais Tavares Amorim6Ana Maria Nunes Botelho7Ana Tereza Ribeiro Vasconcelos8Luiz Gonzaga Paula Almeida9Paul J. Planet10Paul J. Planet11Paul J. Planet12Russolina Benedeta Zingali13Agnes Marie Sá Figueiredo14Bernadete Teixeira Ferreira-Carvalho15Instituto de Microbiologia Paulo de Góes, Universidade Federal do Rio de Janeiro, Rio de Janeiro, BrazilInstituto de Microbiologia Paulo de Góes, Universidade Federal do Rio de Janeiro, Rio de Janeiro, BrazilDepartamento de Microbiologia e Parasitologia, Universidade Federal do Rio Grande do Norte, Natal, BrazilInstituto de Microbiologia Paulo de Góes, Universidade Federal do Rio de Janeiro, Rio de Janeiro, BrazilInstituto de Microbiologia Paulo de Góes, Universidade Federal do Rio de Janeiro, Rio de Janeiro, BrazilInstituto de Microbiologia Paulo de Góes, Universidade Federal do Rio de Janeiro, Rio de Janeiro, BrazilInstituto de Microbiologia Paulo de Góes, Universidade Federal do Rio de Janeiro, Rio de Janeiro, BrazilInstituto de Microbiologia Paulo de Góes, Universidade Federal do Rio de Janeiro, Rio de Janeiro, BrazilLaboratório Nacional de Computação Científica (LNCC), Petrópolis, BrazilLaboratório Nacional de Computação Científica (LNCC), Petrópolis, BrazilDepartment of Pediatrics, Perelman College of Medicine, University of Pennsylvania, Philadelphia, PA, United StatesSackler Institute for Comparative Genomics, American Museum of Natural History, New York, NY, United StatesChildren’s Hospital of Philadelphia, Philadelphia, PA, United StatesUnidade de Espectrometria de Massas e Proteomica – UEMP, Instituto de Bioquímica Médica Leopoldo de Meis, Universidade Federal do Rio de Janeiro, Rio de Janeiro, BrazilInstituto de Microbiologia Paulo de Góes, Universidade Federal do Rio de Janeiro, Rio de Janeiro, BrazilInstituto de Microbiologia Paulo de Góes, Universidade Federal do Rio de Janeiro, Rio de Janeiro, BrazilStreptococcus pyogenes (group A Streptococcus-GAS) is an important pathogen for humans. GAS has been associated with severe and invasive diseases. Despite the fact that these bacteria remain universally susceptible to penicillin, therapeutic failures have been reported in some GAS infections. Many hypotheses have been proposed to explain these antibiotic-unresponsive infections; however, none of them have fully elucidated this phenomenon. In this study, we show that GAS strains have the ability to form antimicrobial persisters when inoculated on abiotic surfaces to form a film of bacterial agglomerates (biofilm-like environment). Our data suggest that efflux pumps were possibly involved in this phenomenon. In fact, gene expression assays by real-time qRT-PCR showed upregulation of some genes associated with efflux pumps in persisters arising in the presence of penicillin. Phenotypic reversion assay and whole-genome sequencing indicated that this event was due to non-inherited resistance mechanisms. The persister cells showed downregulation of genes associated with protein biosynthesis and cell growth, as demonstrated by gene expression assays. Moreover, the proteomic analysis revealed that susceptible cells express higher levels of ribosome proteins. It is remarkable that previous studies have reported the recovery of S. pyogenes viable cells from tissue biopsies of patients presented with GAS invasive infections and submitted to therapy with antibiotics. The persistence phenomenon described herein brings new insights into the origin of therapeutic failures in S. pyogenes infections. Multifactorial mechanisms involving protein synthesis inhibition, cell growth impairment and efflux pumps seem to play roles in the formation of antimicrobial persisters in S. pyogenes.https://www.frontiersin.org/articles/10.3389/fmicb.2021.716628/fullStreptococcus pyogenesdrug refractorypersistersefflux pumpantimicrobial resistanceclinical resistance |
| spellingShingle | Caroline Lopes Martini Amada Zambrana Coronado Maria Celeste Nunes Melo Clarice Neffa Gobbi Úrsula Santos Lopez Marcos Correa de Mattos Thais Tavares Amorim Ana Maria Nunes Botelho Ana Tereza Ribeiro Vasconcelos Luiz Gonzaga Paula Almeida Paul J. Planet Paul J. Planet Paul J. Planet Russolina Benedeta Zingali Agnes Marie Sá Figueiredo Bernadete Teixeira Ferreira-Carvalho Cellular Growth Arrest and Efflux Pumps Are Associated With Antibiotic Persisters in Streptococcus pyogenes Induced in Biofilm-Like Environments Frontiers in Microbiology Streptococcus pyogenes drug refractory persisters efflux pump antimicrobial resistance clinical resistance |
| title | Cellular Growth Arrest and Efflux Pumps Are Associated With Antibiotic Persisters in Streptococcus pyogenes Induced in Biofilm-Like Environments |
| title_full | Cellular Growth Arrest and Efflux Pumps Are Associated With Antibiotic Persisters in Streptococcus pyogenes Induced in Biofilm-Like Environments |
| title_fullStr | Cellular Growth Arrest and Efflux Pumps Are Associated With Antibiotic Persisters in Streptococcus pyogenes Induced in Biofilm-Like Environments |
| title_full_unstemmed | Cellular Growth Arrest and Efflux Pumps Are Associated With Antibiotic Persisters in Streptococcus pyogenes Induced in Biofilm-Like Environments |
| title_short | Cellular Growth Arrest and Efflux Pumps Are Associated With Antibiotic Persisters in Streptococcus pyogenes Induced in Biofilm-Like Environments |
| title_sort | cellular growth arrest and efflux pumps are associated with antibiotic persisters in streptococcus pyogenes induced in biofilm like environments |
| topic | Streptococcus pyogenes drug refractory persisters efflux pump antimicrobial resistance clinical resistance |
| url | https://www.frontiersin.org/articles/10.3389/fmicb.2021.716628/full |
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