Affiliation:
1. Centre for Infection and Immunity, Queen's University Belfast, Medical Biology Centre, Belfast, United Kingdom
2. Institute for Medical Microbiology, Immunology and Hygiene, University of Cologne, Cologne, Germany
3. Laboratorio de Investigación en Agentes Antibacterianos, Departamento de Microbiología, Facultad de Ciencias Biológicas, Universidad de Concepción, Concepción, Chile
Abstract
ABSTRACT
Transcriptional regulators, such as SoxS, RamA, MarA, and Rob, which upregulate the AcrAB efflux pump, have been shown to be associated with multidrug resistance in clinically relevant Gram-negative bacteria. In addition to the multidrug resistance phenotype, these regulators have also been shown to play a role in the cellular metabolism and possibly the virulence potential of microbial cells. As such, the increased expression of these proteins is likely to cause pleiotropic phenotypes.
Klebsiella pneumoniae
is a major nosocomial pathogen which can express the SoxS, MarA, Rob, and RamA proteins, and the accompanying paper shows that the increased transcription of
ramA
is associated with tigecycline resistance (
M. Veleba and T. Schneiders
, Antimicrob. Agents Chemother. 56:4466–4467, 2012). Bioinformatic analyses of the available
Klebsiella
genome sequences show that an additional AraC-type regulator is encoded chromosomally. In this work, we characterize this novel AraC-type regulator, hereby called RarA (Regulator of antibiotic resistance A), which is encoded in
K. pneumoniae
,
Enterobacter
sp. 638,
Serratia proteamaculans
568, and
Enterobacter cloacae
. We show that the overexpression of
rarA
results in a multidrug resistance phenotype which requires a functional AcrAB efflux pump but is independent of the other AraC regulators. Quantitative real-time PCR experiments show that
rarA
(MGH 78578 KPN_02968) and its neighboring efflux pump operon
oqxAB
(KPN_02969_02970) are consistently upregulated in clinical isolates collected from various geographical locations (Chile, Turkey, and Germany). Our results suggest that
rarA
overexpression upregulates the
oqxAB
efflux pump. Additionally, it appears that
oqxR
, encoding a GntR-type regulator adjacent to the
oqxAB
operon, is able to downregulate the expression of the
oqxAB
efflux pump, where OqxR complementation resulted in reductions to olaquindox MICs.
Publisher
American Society for Microbiology
Subject
Infectious Diseases,Pharmacology (medical),Pharmacology