Burkholderia pseudomallei is the causative agent of the often fatal disease melioidosis. Even with accurate diagnosis and rapid therapeutic interventions, mortality rates still range from >9% in northern Australia to >40% in Thailand. The high mortality rates associated with melioidosis have resulted in this bacterium being categorised as a Tier 1 biological agent by the Centers for Disease Control and Prevention (CDC). Therefore understanding the mechanisms of antibiotic resistance and virulence factors in B. pseudomallei is of great importance.
Recovery from melioidosis relies heavily on treatment with ceftazidime (CAZ). Known CAZ resistance mechanisms include amino acid changes that alter the substrate specificity in the class A β–lactamase, PenA, and up-regulation of penA, which can occur by mutations in the promoter region. In the current study we screened clinical B. pseudomallei isolated from relapsed and chronic melioidosis patients in the Northern Territory, Australia, for CAZ resistance mechanisms. We found that the rate of mutant polymorphisms in clinical B. pseudomallei was low (0.9%) although elevated compared with non-clinical B. pseudomallei isolates (0.05%); therefore, the results from the present study supports the continued use of CAZ as first line therapy for primary and recurrent melioidosis.
Many disease manifestations are associated with melioidosis; the mechanisms causing this variation are unknown. Virulence determinants in B. pseudomallei are poorly understood, with bimA-Bm the only virulence target that has been associated with severe clinical outcomes. In the current study we screened clinical B. pseudomallei for putative virulence factors fhaB 1, 2 and 3. We found that fhaB 3 was strongly associated with septic shock, the biggest predictor of mortality in melioidosis patients. Conversely, fhaB 3 was associated with the lack of a skin abscess, which is rarely fatal. These results suggest that fhaB 3 is associated with more severe disease formation and is a virulence determinant in the pathogenesis of B. pseudomallei. The present study is the first to identify fhaB 3 as a virulence factor.