Abstract
Efflux pumps contribute to multidrug resistance in Acinetobacter baumannii due to their ability to expel a wide variety of structurally unrelated compounds. This study aimed to characterize the effect of subinhibitory concentrations of clinically-relevant antibiotics and disinfectants on the promoter activity of members of the Resistance-Nodulation-Division (RND) family in A. baumannii. The promoter regions from three RND efflux pumps (AdeABC, AdeFGH and AdeIJK) and the AdeRS regulatory system from three different A. baumannii strains (ATCC 17961, ATCC 17978, and ATCC 19606) were cloned into a luciferase reporter system (pLPV1Z). Promoter activity was quantitatively assessed in both exponential and stationary phase cultures after exposure to subinhibitory concentrations of four antibiotics from different classes (rifampicin, meropenem, tigecycline and colistin) and two disinfectants (ethanol and chlorhexidine). Subinhibitory concentrations of the compounds tested had variable effects on promoter activity that were highly dependent on the A. baumannii strain, the compound tested and the growth phase. Fold changes in AdeABC promoter activity ranged from 1.97 to 113.7, in AdeFGH from −5.6 to 1.13, in AdeIJK from −2.5 to 2, and in AdeRS from −36.2 to −1.32. Taken together, these results indicate that subinhibitory concentrations of clinically-relevant antibiotics and disinfectants affect the promoter activity of RND family members in A. baumannii in a strain and growth phase dependent manner. These results may have important implications for the treatment of infections caused by A. baumannii.
Highlights
Acinetobacter baumannii is an opportunistic Gram-negative pathogen mainly associated with the healthcare environment, incidence of infections caused by this microorganism in the community is increasing (Leung et al, 2006; Dijkshoorn et al, 2007; Lin and Lan, 2014)
We studied the promoters that control the expression of the operons of three efflux pumps of the RND family (AdeABC, AdeFGH, and AdeIJK) and the twocomponent regulatory system (AdeRS) to explore changes in their expression
Regardless of their basal expression, our study demonstrates that subinhibitory concentrations of clinically-relevant antimicrobials affect the promoter activity of all the members of the RND family included in this study
Summary
Acinetobacter baumannii is an opportunistic Gram-negative pathogen mainly associated with the healthcare environment, incidence of infections caused by this microorganism in the community is increasing (Leung et al, 2006; Dijkshoorn et al, 2007; Lin and Lan, 2014). The primitive function of these secretion systems was the removal of metabolic end products or the expulsion of toxins or quorum-sensing molecules (Helling et al, 2002; Sánchez Díaz, 2003), suggesting that these transporters had a different biological function and were later adapted to the expulsion of antibiotics This confers a non-specificity of substrate and may be related to their ability to actively export multiple, structurally-distinct classes of antimicrobials (Poole, 2002; Sánchez Díaz, 2003). These efflux pumps are widely distributed as they have been identified in several microorganisms (Nikaido, 1994) and the presence of several genes coding for different pumps in bacterial genomes have been reported. Efflux pump overexpression has been associated with acquired resistance (Nikaido, 1994; Sánchez Díaz, 2003), which favors the emergence of mutants with a high degree of resistance (Sánchez Díaz, 2003)
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