Deciphering the Role of RND Efflux Transporters in Burkholderia cenocepacia

Bazzini, Silvia; Udine, Claudia; Saß, Andrea; Pasca, Maria Rosalia; Longo, Francesca; Emiliani, Giovanni; Fondi, Marco; Perrin, Elena; Decorosi, Francesca; Viti, Carlo; Giovannetti, Luciana; Leoni, Livia; Fani, Renato; Riccardi, Giovanna; Mahenthiralingam, Eshwar; Buroni, Silvia

doi:10.1371/journal.pone.0018902

Cited by 68 publications

(70 citation statements)

References 45 publications

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“…Previous data revealed that RND-4 efflux pump is involved in the extrusion of different toxic compounds, including some antibiotics. Moreover, in our recent paper, transcriptomic and phenomic analyses suggested that the deletion of RND-4 coding genes might have a "pleiotropic" effect in the B. cenocepacia J2315 metabolism [14]. These findings were in part confirmed by the proteomic analysis performed in this study.…”

Section: Discussionsupporting

confidence: 82%

RND-4 efflux transporter gene deletion in Burkholderia cenocepacia J2315: a proteomic analysis

Gamberi

Rocchiccioli²,

Papaleo³

et al. 2013

J Proteome Sci Comput Biol

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Background: The Burkholderia cenocepacia J2315 is Gram-negative bacterium that is a pathogen for cystic fibrosis (CF) patients. It displays a high-level of resistance to most antimicrobial drugs. In Gram-negative bacteria, the ResistanceNodulation-Cell Division (RND) transporter family has a poorly understood role in multidrug resistance. In a previous publication we analysed the RND-4 and RND-9 transporters by microarray analysis. The obtained results suggested that only RND-4 contributes to the antibiotic resistance. The aim of this study was to investigate the role of this efflux transporter from a proteomic point of view.

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Section: Discussionsupporting

confidence: 82%

RND-4 efflux transporter gene deletion in Burkholderia cenocepacia J2315: a proteomic analysis

Gamberi

Rocchiccioli²,

Papaleo³

et al. 2013

J Proteome Sci Comput Biol

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“…cepacia complex bacteria are traditionally considered to be intrinsically resistant to aminoglycosides through a number of different resistance mechanisms, including the resistancenodulation-division (RND) efflux systems (14). Confirming this fact, in our series of experiments, we found a near-complete absence of effect of tobramycin at a concentration of 8 g/ml (representing systemic drug concentrations) on biofilm thickness and viability.…”

Section: Discussionsupporting

confidence: 77%

Activity of Tobramycin against Cystic Fibrosis Isolates of Burkholderia cepacia Complex Grown as Biofilms

Kennedy

Beaudoin

Yau

et al. 2016

Antimicrob Agents Chemother

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f Pulmonary infection with Burkholderia cepacia complex in cystic fibrosis (CF) patients is associated with more-rapid lung function decline and earlier death than in CF patients without this infection. In this study, we used confocal microscopy to visualize the effects of various concentrations of tobramycin, achievable with systemic and aerosolized drug administration, on mature B. cepacia complex biofilms, both in the presence and absence of CF sputum. After 24 h of growth, biofilm thickness was significantly reduced by exposure to 2,000 g/ml of tobramycin for Burkholderia cepacia, Burkholderia multivorans, and Burkholderia vietnamiensis; 200 g/ml of tobramycin was sufficient to reduce the thickness of Burkholderia dolosa biofilm. With a more mature 48-h biofilm, significant reductions in thickness were seen with tobramycin at concentrations of >100 g/ml for all Burkholderia species. In addition, an increased ratio of dead to live cells was observed in comparison to control with tobramycin concentrations of >200 g/ml for B. cepacia and B. dolosa (24 h) and >100 g/ml for Burkholderia cenocepacia and B. dolosa (48 h). Although sputum significantly increased biofilm thickness, tobramycin concentrations of 1,000 g/ml were still able to significantly reduce biofilm thickness of all B. cepacia complex species with the exception of B. vietnamiensis. In the presence of sputum, 1,000 g/ml of tobramycin significantly increased the dead-to-live ratio only for B. multivorans compared to control. In summary, although killing is attenuated, high-dose tobramycin can effectively decrease the thickness of B. cepacia complex biofilms, even in the presence of sputum, suggesting a possible role as a suppressive therapy in CF.

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“…RNDs 6 and 7 are twin pumps encoded by the same operon, similar to MdtBC of E. coli (127,611). Inactivation of the rnd-4 gene led to a 4-to 8-fold increase in susceptibility to aztreonam, ciprofloxacin, levofloxacin, gentamicin, tobramycin, and chloramphenicol (614,615). With 16 RND pumps present in B. cenocepacia strain J2315, their differential roles in drug resistance of planktonic and biofilm cells were investigated (613).…”

Section: Burkholderia Sppmentioning

confidence: 99%

“…Upregulation of multiple proteins, including an uncharacterized RND pump and the OmpA and CarO OM proteins, also occurs in A. baumannii biofilms (894). However, despite the overall positive impact of drug exporters on biofilm formation, the inactivation of two RND pumps (i.e., RND-4, RND-9, or both) in a B. cenocepacia strain enhanced biofilm formation (615). These observations of the efflux pump's impact on biofilm formation may partially be attributable to the altered levels of certain signaling molecules in the mutant strains.…”

Section: Role Of Efflux Pumps In Biofilm Formation and Resistancementioning

confidence: 99%

The Challenge of Efflux-Mediated Antibiotic Resistance in Gram-Negative Bacteria

2015

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SUMMARY The global emergence of multidrug-resistant Gram-negative bacteria is a growing threat to antibiotic therapy. The chromosomally encoded drug efflux mechanisms that are ubiquitous in these bacteria greatly contribute to antibiotic resistance and present a major challenge for antibiotic development. Multidrug pumps, particularly those represented by the clinically relevant AcrAB-TolC and Mex pumps of the resistance-nodulation-division (RND) superfamily, not only mediate intrinsic and acquired multidrug resistance (MDR) but also are involved in other functions, including the bacterial stress response and pathogenicity. Additionally, efflux pumps interact synergistically with other resistance mechanisms (e.g., with the outer membrane permeability barrier) to increase resistance levels. Since the discovery of RND pumps in the early 1990s, remarkable scientific and technological advances have allowed for an in-depth understanding of the structural and biochemical basis, substrate profiles, molecular regulation, and inhibition of MDR pumps. However, the development of clinically useful efflux pump inhibitors and/or new antibiotics that can bypass pump effects continues to be a challenge. Plasmid-borne efflux pump genes (including those for RND pumps) have increasingly been identified. This article highlights the recent progress obtained for organisms of clinical significance, together with methodological considerations for the characterization of MDR pumps.

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Deciphering the Role of RND Efflux Transporters in Burkholderia cenocepacia

Cited by 68 publications

References 45 publications

RND-4 efflux transporter gene deletion in Burkholderia cenocepacia J2315: a proteomic analysis

RND-4 efflux transporter gene deletion in Burkholderia cenocepacia J2315: a proteomic analysis

Activity of Tobramycin against Cystic Fibrosis Isolates of Burkholderia cepacia Complex Grown as Biofilms

The Challenge of Efflux-Mediated Antibiotic Resistance in Gram-Negative Bacteria

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