Infection in CF patients may result in asymptomatic carriage, but often

leads to a rapid decline of the lung function and in some cases to the “”cepacia syndrome”", characterized by necrotizing pneumonia and sepsis [4]. B. cenocepacia and other members of the Bcc demonstrate high-levels of intrinsic resistance to most clinically relevant antibiotics, complicating the treatment of the infection [5]. Multi-drug resistance in CF isolates is defined as resistance to all of the agents in two of three classes of antibiotics, such as quinolones, aminoglycosides, and β-lactam agents, including monobactams and carbapenems [6]. Multiple antibiotic resistances in Bcc bacteria have been attributed to reduced permeability of the bacterial outer membrane [7–9], expression of antibiotic modifying enzymes [10], SN-38 and alteration of cellular

targets [11]. Information relating to the contribution that drug efflux systems play in the drug resistance of Bcc bacteria is limited, as only a few multi-drug efflux pumps have been described to date in some clinical isolates [12–14]. In contrast, the contribution of multidrug efflux systems buy TPX-0005 to antibiotic resistance in clinical isolates of Pseudomonas aeruginosa, another CF pathogen, is well documented. Two P. aeruginosa efflux pumps, MexAB-OprM and MexXY-OprM, contribute to intrinsic multidrug resistance, while MexCD-OprJ and MexEF-OprN are responsible for the acquired antimicrobial resistance of different mutant strains [15]. RND transporters are important mediators of multi-drug resistance in Gram-negative bacteria [16]. RND transporters form protein complexes that span both the cytoplasmic and outer membrane. The complex Tideglusib comprises a cytoplasmic membrane transporter protein, a periplasmic-exposed

membrane adaptor protein, and an outer-membrane channel protein. The Escherichia coli AcrAB-TolC and the P. aeruginosa MexAB-OprM complexes are extremely well characterized and the three-dimensional structures of various components have been resolved [17–21]. Two RND type multi-drug efflux pumps, AmrAB-OprA and BpeAB-OprB, have been described in Burkholderia pseudomallei (the causative agent of melioidosis) and both confer resistance to aminoglycosides and macrolides [22, 23]. The contribution of BpeAB-OprB Dapagliflozin and AmrAB-OprA, to the intrinsic resistance of B. pseudomallei to gentamicin, streptomycin and erythromycin explains why aminoglycoside-β-lactam combinations, which are commonly used to treat suspected cases of community-acquired sepsis in any part of the world, are ineffective for the treatment of melioidosis [24]. Furthermore, the transport of acyl homoserine lactones, involved in quorum-sensing systems of B. pseudomallei, also requires the BpeAB-OprB efflux pump [25]. Thus, targeted inhibition of BpeAB-OprB could be therapeutically beneficial.