The AcrAB RND efflux system from the live vaccine strain ofFrancisella tularensisis a multiple drug efflux system that is required for virulence in mice

Abstract

The ability of bacterial pathogens to infect and cause disease is dependent upon their ability to resist antimicrobial components produced by their host, such as bile acids, fatty acids and other detergent-like molecules, and products of the innate immune system (e.g. cationic antimicrobial peptides). Bacterial resistance to the antimicrobial effects of such compounds is often mediated by active efflux systems belonging to the resistance-nodulation-division (RND) family of transporters. RND efflux systems have been implicated in antibiotic resistance and virulence extending their clinical relevance. In this report the hypothesis that the Francisella tularensis AcrAB RND efflux system contributes to antimicrobial resistance and pathogenesis has been tested. A null mutation was generated in the gene encoding the AcrB RND efflux pump protein of the live vaccine strain of F. tularensis. The resulting mutant exhibited increased sensitivity to multiple antibiotics and antimicrobial compounds. Murine challenge experiments revealed that the acrB mutant was attenuated. Collectively these results suggest that the F. tularensis AcrAB RND efflux system encodes a multiple drug efflux system that is important for virulence.

Subversion of Host Recognition and Defense Systems by Francisella spp

“…The AcrAB inner membrane efflux platform (30), coupled with the TolC outer membrane transporter (91,178), forms a pump that facilitates the active efflux of toxic compounds and detergents from the bacteria, preventing their antimicrobial action. This multidrug efflux pump is important for Francisella resistance to ␤-lactams, tetracyclines, aminoglycosides, quinolones, detergents (notably bile salts), and antimicrobial dyes (30,91).…”

“…This multidrug efflux pump is important for Francisella resistance to ␤-lactams, tetracyclines, aminoglycosides, quinolones, detergents (notably bile salts), and antimicrobial dyes (30,91). Highlighting the importance of this system in pathogenesis, mutants with mutations in pump components are severely attenuated in vivo (30,91,178).…”

“…This multidrug efflux pump is important for Francisella resistance to ␤-lactams, tetracyclines, aminoglycosides, quinolones, detergents (notably bile salts), and antimicrobial dyes (30,91). Highlighting the importance of this system in pathogenesis, mutants with mutations in pump components are severely attenuated in vivo (30,91,178). While the AcrAB/TolC system is known to provide resistance against host antimicrobial peptides in bacteria (95) and it is assumed that Francisella mutants would be more sensitive to host-derived antimicrobials during infection, to the best of our knowledge this has not been directly tested.…”

RamA, a Member of the AraC/XylS Family, Influences Both Virulence and Efflux inSalmonella entericaSerovar Typhimurium

“…AcrAB-TolC and homologous efflux systems are important in the pathogenicity of Salmonella enterica serovar Typhimurium (10, 14) and other bacterial species (11,15,16). Recent work by our laboratory in S. Typhimurium has shown that following the disruption of acrA, acrB, or tolC, a phenotype of decreased pathogenicity was associated with global changes in expression of genes involved in virulence (such as those in SPI-1), chemotaxis, and motility (70).…”

Interactions of Francisella Tularensis With Components of the Host Fibrinolytic System

“…As might be expected, being in contact with host plasma proteins outside of the cell leaves FT exposed to components of innate immunity, such as complement proteins, antimicrobial peptides, and various opsonizing proteins. Despite all of these potential killing mechanisms of the mammalian host, FT appears not only resistant to these threats (41,97,105), but in some instances has been shown to use such host proteins to its advantage. In one such example, it has been suggested by Ben Nasr and Klimpel that FT circumvents the assembly of the complement membrane attack complex on its surface while enabling complement-mediated opsonophagocytosis by using host factor H (63).…”