Acinetobacter baumannii research group FOR 2251

Role of AdeRS and EsvA in the regulation of multidrug resistance in A. baumannii

Antibiotic resistance in bacteria is fast becoming one of the biggest threats to modern medicine; in the hospital setting modern medicine has introduced a subgroup of patients that are severely immunocompromised and subsequently very susceptible to infection. This has led to an ever increasing use of antimicrobials, with a corresponding selective pressure, followed by the emergence of so called “super bugs” that are resistant to most, if not all, available antimicrobials. The era of untreatable infections is now upon us.  It is in this background that Acinetobacter baumannii has emerged as a serious hospital-acquired pathogen.

A. baumannii has gained notoriety for its multi-drug (MDR), pan-drug, and in some cases extreme-drug resistance, with carbapenem- and colistin-resistance causing the greatest concern. Now we are faced with an organism that is sometimes untreatable. This MDR phenotype is strongly associated with particular clonal lineages, and is mediated through acquired mechanisms such as Class-D oxacillinases, and mutations in genes encoding the antibiotic targets. In addition there are intrinsic mechanisms such as drug efflux combined with reduced permeability. Of the several different classes of efflux pumps, in Gram-negative microorganisms the RND (resistance nodulation and cell division) pumps pose the greatest threat. These tri-partite pumps span the inner and outer membranes and typically have a broad substrate specificity and their over-expression can lead to an MDR phenotype; resistance to fluoroquinolones, beta-lactams, tetracyclines, aminoglycosides, macrolides and trimethoprim as well as antiseptics and disinfectants like triclosan and benzalkonium chloride.

Currently there are three RND pumps characterized in A. baumannii: AdeABC, AdeFGH and AdeIJK. Expression of these pumps are regulated by a two-component regulatory system (AdeRS), a LysR-type transcriptional regulator (AdeL) or a TetR type regulator (AdeN), respectively. Analysis of A. baumannii genomes reveals there are several uncharacterised RND efflux pump systems.

Our goal is to investigate these RND efflux pumps, looking at their regulation and expression in clinical isolates, and to determine their relative contribution to the MDR phenotype.