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oai:repisalud.isciii.es:20.500.12105/73322024-11-28T18:09:48Zcom_20.500.12105_2052com_20.500.12105_2051com_20.500.12105_15322col_20.500.12105_19609col_20.500.12105_16962col_20.500.12105_16970

00925njm 22002777a 4500 dc Rodríguez-Arce, Irene author Martí, Sara author Euba, Begoña author Fernández-Calvet, Ariadna author Moleres, Javier author López-López, Nahikari author Barberán, Montserrat author Ramos-Vivas, José author Tubau, Fe author Losa, Carmen author Ardanuy, Carmen author Leiva, José author Yuste, Jose Enrique author Garmendia, Junkal author 2017-06 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. Front Cell Infect Microbiol. 2017 Jun;7:266. 10.3389/fcimb.2017.00266 2235-2988 Frontiers in cellular and infection microbiology 28676846 http://hdl.handle.net/20.500.12105/7332 Haemophilus influenzae Airway infection Antibiotic resistance Bacterial morphology Thymidine auxotrophy Thymidine uptake Thymidylate synthase 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