Interconexión entre la resitencia intrínseca y adquirida a quinolonas en Stenotrophomonas maltophilia
Author
García León, GuillermoEntity
CSIC. Centro Nacional de Biotecnología (CNB)Date
2014-06-17Subjects
Resistiencia a los medicamentos - Tesis doctorales; Quinolonas - Tesis doctorales; Bacterias Gram-negativas - Tesis doctorales; Biología y Biomedicina / BiologíaNote
Tesis doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Ciencias, Departamento de Biología Molecular. Fecha de lectura: 17-06-2014Esta obra está bajo una licencia de Creative Commons Reconocimiento-NoComercial-SinObraDerivada 4.0 Internacional.
Abstract
Stenotrophomonas maltophilia is an opportunistic pathogen of growing relevance due to
its increasing prevalence in the nosocomial environment. A typical feature of S.
maltophilia is its intrinsic resistant phenotype to a great number of antibiotics,
quinolones included, which makes difficult the treatment of the infected patients.
Quinolones are a family of synthetic antibiotics which targets are the bacterial
topoisomerases. In all bacteria, acquired resistance to these antibiotics usually comes
through mutations in the topoisomerase genes. However, S. maltophilia is an exception
to this rule (Ribera et al., 2002; Valdezate et al., 2002; Valdezate et al., 2005).
In the first part of this work we studied the contribution of the best-known determinants
of intrinsic quinolone resistance in S. maltophilia, the SmeDEF efflux pump and the
SmQnr protein, to the development of acquired quinolone resistance. Comparisons were
made of the apparent mutation frequencies for quinolone resistance and the types of
mutants selected by quinolones in the wild-type S. maltophilia strain D457 and in
mutants lacking either SmQnr, either SmeDEF, or both. Mutation frequencies were
found to be related to the intrinsic resistome and also depended on the concentration of
the selector. Most mutants had phenotypes compatible with the overexpression of
multidrug efflux pump(s), being SmeDEF overexpression the most common cause of
quinolone resistance. Whole genome sequencing showed that mutations of the SmeRv
regulator, which result in the overexpression of the efflux pump SmeVWX, were the
cause of quinolone resistance in mutants not overexpressing SmeDEF. In addition, we
have determined that the inactivation of SmeDEF and/or SmQnr widens the mutant
selection windows for some quinolones by reducing their MICs. This indicates that this
inactivation might increase the chances for selecting resistant mutants at low antibiotic
concentrations.
In the second part of this work we analyzed the participation of SmeDEF, SmQnr and
SmeVWX in the quinolone resistance of a collection of S. maltophilia clinical isolates.
In agreement with previous data (Alonso and Martinez, 2001), we showed that SmeDEF
overexpression has an important role in low quinolone susceptibility in clinical isolates.
The SmeVWX overexpression was also identified in two of the isolates. This is the first
time that overexpression of the SmeVWX efflux pump is associated to quinolone
resistance in clinical S. maltophilia isolates.
In the third part of this work we analyzed the function of SmeDEF and SmQnr in one of
the natural habitats of S. maltophilia, the plant roots. We determined that the deletion of
SmeDEF impairs S. maltophilia colonization of plant roots, which is in agreement with
previous data of our laboratory showing plant-produced flavonoids to be inducers of
SmeDEF expression and not antibiotics. This showed that one original function of
SmeDEF efflux pump is on the colonization of plant roots. Overexpression of SmQnr
also impairs this colonization, but we do not know the reason underlying this behavior
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