Klebsiella pneumoniae AcrAB Efflux Pump Contributes to Antimicrobial Resistance and Virulence

Abstract

Respiratory infections caused by Klebsiella pneumoniae are characterized by high rates of mortality and morbidity. Management of these infections is often difficult, due to the high frequency of strains that are resistant to multiple antimicrobial agents. Multidrug efflux pumps play a major role as a mechanism of antimicrobial resistance in Gram-negative pathogens. In the present study, we investigated the role of the K. pneumoniae AcrRAB operon in antimicrobial resistance and virulence by using isogenic knockouts deficient in the AcrB component and the AcrR repressor, both derived from the virulent strain 52145R. We demonstrated that the AcrB knockout was more susceptible, not only to quinolones, but also to other antimicrobial agents, including ␤-lactams, than the wild-type strain and the AcrR knockout. We further showed that the AcrB knockout was more susceptible to antimicrobial agents present in human bronchoalveolar lavage fluid and to human antimicrobial peptides than the wild-type strain and the AcrR knockout. Finally, the AcrB knockout exhibited a reduced capacity to cause pneumonia in a murine model, in contrast to the wild-type strain. The results of this study suggest that, in addition to contributing to the multidrug resistance phenotype, the AcrAB efflux pump may represent a novel virulence factor required for K. pneumoniae to resist innate immune defense mechanisms of the lung, thus facilitating the onset of pneumonia.

Antimicrobial Resistance and Virulence: a Successful or Deleterious Association in the Bacterial World?

“…This is an important example that establishes a link between antibiotic resistance and AcrABTolC-mediated virulence in S. enterica. Padilla et al also showed that a K. pneumoniae acrAB knockout mutant exhibited a lower capacity than the wild-type strain to cause pneumonia in a murine model (90). Bialek et al found that overexpression of the AcrAB efflux system in the Caenorhabditis elegans model is linked to an increased virulence potential in K. pneumoniae (91).…”

Polymyxins: Antibacterial Activity, Susceptibility Testing, and Resistance Mechanisms Encoded by Plasmids or Chromosomes

“…The role of efflux in colistin resistance is not well understood, but several studies suggested the involvement of efflux pumps in colistin resistance. Mutations in kpnEF and acrAB, encoding components of efflux pumps, may actually lead to a 2-fold decrease of the MIC of colistin and increase bacterial survival in the presence of a low concentration of polymyxins (163,164). Addition to the test medium of low doses of the efflux pump inhibitor carbonyl cyanide m-chlorophenylhydrazone (CCCP) decreased the MICs for resistant strains (128-to 512-fold reductions) and partially or completely inhibited the regrowth of resistant subpopulations (165).…”

Regulation of the AcrAB multidrug efflux pump in Salmonella enterica serovar Typhimurium in response to indole and paraquat

“…A Salmonella acrB mutant strain showed decreased invasion and survival in mouse monocyte macrophages (Buckley et al, 2006). Klebsiella pneumoniae AcrAB contributes to resistance to antimicrobial peptides, and an AcrB knockout mutant exhibited a reduced capacity to cause pneumonia in a murine model (Padilla et al, 2010). The acrAB regulation mechanism must be examined to understand the physiological role of AcrAB.…”