Abstract
Multidrug resistance in Gram-negative bacteria can arise by the over-expression of multidrug efflux pumps, which can extrude a wide range of antibiotics. Here we describe the ancestral Haemophilus influenzae efflux pump AcrB (AcrB-Hi). We performed a phylogenetic analysis of hundreds of RND-type transporters. We found that AcrB-Hi is a relatively ancient efflux pump, which nonetheless can export the same range of antibiotics as its evolved colleague from Escherichia coli. AcrB-Hi was not inhibited by the efflux pump inhibitor ABI-PP, and could export bile salts weakly. This points to an environmental adaptation of RND transporters. We also explain the sensitivity of H. influenzae cells to β-lactams and novobiocin by the outer membrane porin OmpP2. This porin counterbalances the AcrB-Hi efflux by leaking the drugs back into the cells. We hypothesise that multidrug recognition by RND-type pumps is not an evolutionarily acquired ability, and has been present since ancient promiscuous transporters.
Highlights
Multidrug resistance in Gram-negative bacteria can arise by the over-expression of multidrug efflux pumps, which can extrude a wide range of antibiotics
To investigate the RND efflux pump AcrB expressed in H. influenzae (AcrB-Hi), we decided to compare the pump to the probably most studied RND multidrug efflux pump AcrB from E. coli (AcrB-Ec)
We found that acrB is the only RND transporter gene (HI0895) in the Haemophilus influenzae Rd KW20 genome with a translated length of 1032 amino acids (AcrB-Ec has 1049 amino acids)
Summary
Multidrug resistance in Gram-negative bacteria can arise by the over-expression of multidrug efflux pumps, which can extrude a wide range of antibiotics. Multidrug resistance (MDR) in Gram-negative bacteria can be caused solely by the overexpression of antibiotic efflux pumps These pumps render several or all classes of antibiotics commercially available today ineffective[12]. Such a multidrug efflux pump (called AcrB) belonging to the resistance-nodulationdivision (RND) superfamily is expressed in H. influenzae cells. H. influenzae AcrB (AcrB-Hi) is an efflux pump that was shown to expel several antibiotics and dyes similar to Escherichia coli AcrB (AcrB-Ec)[13] This efflux pump has been described previously to cause macrolide resistance[14], relatively little is known about the role of AcrB in Hib drug resistance, in addition to its large outer membrane protein OmpP2. We hypothesise that multidrug recognition by multidrug efflux pumps did not increase during evolution and that the ability to export chemically different compounds is an intrinsic property since ancient transporters
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