Roles of DHA2 family transporters in drug resistance and iron homeostasis in Acinetobacter spp.

Background: Acinetobacterbaumannii is a major cause of nosocomial infections worldwide due to its fitness within clinical settings and recalcitrance to conventional therapies. The drug: H⁺ antiporter 2 (DHA2) family export systems encoded by A. baumannii were investigated for their roles in promoting the success ofthis organism as a human pathogen. Methods: Bioinformatic tools were used to identify the DHA2 family transporters encoded by Acinetobacter spp. and establish their phylogenetic relationships. The drug resistance phenotypes conferred by the transporters were tested using both heterologously expressed proteins in Escherichia coli and Acinetobacter deletion mutants. The transcriptional responses of DHA2 family transporter genes to their substrates were established by qRT-PCR. Results: Six highly conserved DHA2 family proteins were identified in A. baumannii. Drug resistance phenotypes were established for two DHA2 family transporters. The expression of a third DHA2 family protein is highly responsive to the availability of iron. The gene encoding this protein is located within a putative siderophore biosynthesis locus, suggesting a physiological role in iron uptake, possibly via the export of a siderophore. Conclusions: These results highlight functions for DHA2 family proteins in both drug resistance and the maintenance of stable cellular physiology, emphasizing their importance in A. baumannii infections.