Inactivation of the thymidylate synthase thyA in non-typeable Haemophilus influenzae modulates antibiotic resistance and has a strong impact on its interplay with the host airways.

Antibacterial treatment with cotrimoxazol (TxS), a combination of trimethoprim and sulfamethoxazole, generates resistance by, among others, acquisition of thymidine auxotrophy associated with mutations in the thymidylate synthase gene thyA, which can modify the biology of infection. The opportunisti...

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Autores: Rodríguez Arce, Irene, Martí Martí, Sara, Euba, Begoña, Fernández Calvet, Ariadna, Moleres, Javier, López López, Nahikari, Barberán, Montserrat, Ramos Vivas, José, Tubau, Fe, Losa, Carmen, Ardanuy Tisaire, María Carmen, Leiva, José, Juste, José E., Garmendia, Junkal
Formato: artículo
Estado:Versión publicada
Fecha de publicación:2017
País:España
Recursos:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repositorio:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat:2445/140434
Acesso em linha:https://hdl.handle.net/2445/140434
Access Level:acceso abierto
Palavra-chave:Antibiòtics
Efecte dels medicaments sobre els microorganismes
Influenzavirus
Antibiotics
Effect of drugs on microorganisms
Influenza viruses
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spelling Inactivation of the thymidylate synthase thyA in non-typeable Haemophilus influenzae modulates antibiotic resistance and has a strong impact on its interplay with the host airways.Rodríguez Arce, IreneMartí Martí, SaraEuba, BegoñaFernández Calvet, AriadnaMoleres, JavierLópez López, NahikariBarberán, MontserratRamos Vivas, JoséTubau, FeLosa, CarmenArdanuy Tisaire, María CarmenLeiva, JoséJuste, José E.Garmendia, JunkalAntibiòticsEfecte dels medicaments sobre els microorganismesInfluenzavirusAntibioticsEffect of drugs on microorganismsInfluenza virusesAntibacterial treatment with cotrimoxazol (TxS), a combination of trimethoprim and sulfamethoxazole, generates resistance by, among others, acquisition of thymidine auxotrophy associated with mutations in the thymidylate synthase gene thyA, which can modify the biology of infection. The opportunistic pathogen non-typeable Haemophilus influenzae (NTHi) is frequently encountered in the lower airways of chronic obstructive pulmonary disease (COPD) patients, and associated with acute exacerbation of COPD symptoms. Increasing resistance of NTHi to TxS limits its suitability as initial antibacterial against COPD exacerbation, although its relationship with thymidine auxotrophy is unknown. In this study, the analysis of 2,542 NTHi isolates recovered at Bellvitge University Hospital (Spain) in the period 2010-2014 revealed 119 strains forming slow-growing colonies on the thymidine low concentration medium Mueller Hinton Fastidious, including one strain isolated from a COPD patient undergoing TxS therapy that was a reversible thymidine auxotroph. To assess the impact of thymidine auxotrophy in the NTHi-host interplay during respiratory infection, thyA mutants were generated in both the clinical isolate NTHi375 and the reference strain RdKW20. Inactivation of the thyA gene increased TxS resistance, but also promoted morphological changes consistent with elongation and impaired bacterial division, which altered H. influenzae self-aggregation, phosphorylcholine level, C3b deposition, and airway epithelial infection patterns. Availability of external thymidine contributed to overcome such auxotrophy and TxS effect, potentially facilitated by the nucleoside transporter nupC. Although, thyA inactivation resulted in bacterial attenuation in a lung infection mouse model, it also rendered a lower clearance upon a TxS challenge in vivo. Thus, our results show that thymidine auxotrophy modulates both the NTHi host airway interplay and antibiotic resistance, which should be considered at the clinical setting for the consequences of TxS administration.Frontiers Media2019201920172019info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersion19 p.application/pdfhttps://hdl.handle.net/2445/140434Articles publicats en revistes (Medicina)reponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)InglésReproducció del document publicat a: https://doi.org/10.3389/fcimb.2017.00266Frontiers in Cellular and Infection Microbiology, 2017, vol. 7, p. 266https://doi.org/10.3389/fcimb.2017.00266cc-by (c) Rodríguez Arce, Irene et al., 2017http://creativecommons.org/licenses/by/3.0/esinfo:eu-repo/semantics/openAccessoai:recercat.cat:2445/1404342026-05-29T05:05:01Z
dc.title.none.fl_str_mv Inactivation of the thymidylate synthase thyA in non-typeable Haemophilus influenzae modulates antibiotic resistance and has a strong impact on its interplay with the host airways.
title Inactivation of the thymidylate synthase thyA in non-typeable Haemophilus influenzae modulates antibiotic resistance and has a strong impact on its interplay with the host airways.
spellingShingle Inactivation of the thymidylate synthase thyA in non-typeable Haemophilus influenzae modulates antibiotic resistance and has a strong impact on its interplay with the host airways.
Rodríguez Arce, Irene
Antibiòtics
Efecte dels medicaments sobre els microorganismes
Influenzavirus
Antibiotics
Effect of drugs on microorganisms
Influenza viruses
title_short Inactivation of the thymidylate synthase thyA in non-typeable Haemophilus influenzae modulates antibiotic resistance and has a strong impact on its interplay with the host airways.
title_full Inactivation of the thymidylate synthase thyA in non-typeable Haemophilus influenzae modulates antibiotic resistance and has a strong impact on its interplay with the host airways.
title_fullStr Inactivation of the thymidylate synthase thyA in non-typeable Haemophilus influenzae modulates antibiotic resistance and has a strong impact on its interplay with the host airways.
title_full_unstemmed Inactivation of the thymidylate synthase thyA in non-typeable Haemophilus influenzae modulates antibiotic resistance and has a strong impact on its interplay with the host airways.
title_sort Inactivation of the thymidylate synthase thyA in non-typeable Haemophilus influenzae modulates antibiotic resistance and has a strong impact on its interplay with the host airways.
dc.creator.none.fl_str_mv Rodríguez Arce, Irene
Martí Martí, Sara
Euba, Begoña
Fernández Calvet, Ariadna
Moleres, Javier
López López, Nahikari
Barberán, Montserrat
Ramos Vivas, José
Tubau, Fe
Losa, Carmen
Ardanuy Tisaire, María Carmen
Leiva, José
Juste, José E.
Garmendia, Junkal
author Rodríguez Arce, Irene
author_facet Rodríguez Arce, Irene
Martí Martí, Sara
Euba, Begoña
Fernández Calvet, Ariadna
Moleres, Javier
López López, Nahikari
Barberán, Montserrat
Ramos Vivas, José
Tubau, Fe
Losa, Carmen
Ardanuy Tisaire, María Carmen
Leiva, José
Juste, José E.
Garmendia, Junkal
author_role author
author2 Martí Martí, Sara
Euba, Begoña
Fernández Calvet, Ariadna
Moleres, Javier
López López, Nahikari
Barberán, Montserrat
Ramos Vivas, José
Tubau, Fe
Losa, Carmen
Ardanuy Tisaire, María Carmen
Leiva, José
Juste, José E.
Garmendia, Junkal
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Antibiòtics
Efecte dels medicaments sobre els microorganismes
Influenzavirus
Antibiotics
Effect of drugs on microorganisms
Influenza viruses
topic Antibiòtics
Efecte dels medicaments sobre els microorganismes
Influenzavirus
Antibiotics
Effect of drugs on microorganisms
Influenza viruses
description Antibacterial treatment with cotrimoxazol (TxS), a combination of trimethoprim and sulfamethoxazole, generates resistance by, among others, acquisition of thymidine auxotrophy associated with mutations in the thymidylate synthase gene thyA, which can modify the biology of infection. The opportunistic pathogen non-typeable Haemophilus influenzae (NTHi) is frequently encountered in the lower airways of chronic obstructive pulmonary disease (COPD) patients, and associated with acute exacerbation of COPD symptoms. Increasing resistance of NTHi to TxS limits its suitability as initial antibacterial against COPD exacerbation, although its relationship with thymidine auxotrophy is unknown. In this study, the analysis of 2,542 NTHi isolates recovered at Bellvitge University Hospital (Spain) in the period 2010-2014 revealed 119 strains forming slow-growing colonies on the thymidine low concentration medium Mueller Hinton Fastidious, including one strain isolated from a COPD patient undergoing TxS therapy that was a reversible thymidine auxotroph. To assess the impact of thymidine auxotrophy in the NTHi-host interplay during respiratory infection, thyA mutants were generated in both the clinical isolate NTHi375 and the reference strain RdKW20. Inactivation of the thyA gene increased TxS resistance, but also promoted morphological changes consistent with elongation and impaired bacterial division, which altered H. influenzae self-aggregation, phosphorylcholine level, C3b deposition, and airway epithelial infection patterns. Availability of external thymidine contributed to overcome such auxotrophy and TxS effect, potentially facilitated by the nucleoside transporter nupC. Although, thyA inactivation resulted in bacterial attenuation in a lung infection mouse model, it also rendered a lower clearance upon a TxS challenge in vivo. Thus, our results show that thymidine auxotrophy modulates both the NTHi host airway interplay and antibiotic resistance, which should be considered at the clinical setting for the consequences of TxS administration.
publishDate 2017
dc.date.none.fl_str_mv 2017
2019
2019
2019
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/140434
url https://hdl.handle.net/2445/140434
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Reproducció del document publicat a: https://doi.org/10.3389/fcimb.2017.00266
Frontiers in Cellular and Infection Microbiology, 2017, vol. 7, p. 266
https://doi.org/10.3389/fcimb.2017.00266
dc.rights.none.fl_str_mv cc-by (c) Rodríguez Arce, Irene et al., 2017
http://creativecommons.org/licenses/by/3.0/es
info:eu-repo/semantics/openAccess
rights_invalid_str_mv cc-by (c) Rodríguez Arce, Irene et al., 2017
http://creativecommons.org/licenses/by/3.0/es
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv 19 p.
application/pdf
dc.publisher.none.fl_str_mv Frontiers Media
publisher.none.fl_str_mv Frontiers Media
dc.source.none.fl_str_mv Articles publicats en revistes (Medicina)
reponame:Recercat. Dipósit de la Recerca de Catalunya
instname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
instname_str Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
reponame_str Recercat. Dipósit de la Recerca de Catalunya
collection Recercat. Dipósit de la Recerca de Catalunya
repository.name.fl_str_mv
repository.mail.fl_str_mv
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