PNAS-publication: Targeted enzymes disrupt infection pathway

Infection by Burkholderia cenocepacia in immunocompromised individuals and people with cystic fibrosis has been correlated with poor patient prognosis. The increasing occurrence of B. cenocepacia in such individuals suggests that the effectiveness of antibiotics used to combat this human pathogen is on the decline. Gudrun Koch and colleagues from the university of Groningen, Groningen Research Institute of Pharmacy, investigated the action of the Pseudomonas aeruginosa enzyme, PvdQ, as a possible alternative to antibiotics because of the enzyme’s ability to disrupt quorum sensing – a bacterial culture’s mechanism for coordinating infection.

The authors introduced two point mutations into PvdQ that altered the structure of the enzyme’s active site, changing its target substrate to C8-HSL, the primary quorum sensing inducer in Burkholderia species. The altered PvdQ enzyme reduced the concentration of C8-HSL in B. cenocepacia cultures 48.5-fold when added exogenously and also rescued a population of Galleria mellonella when the larvae were infected with B. cenocepacia that produced the mutant PvdQ. The authors demonstrate that an enzyme produced by bacteria that disrupts quorum sensing can be altered to target the quorum-sensing substrate of a different bacterial species, suggesting that the technique can be used as a potential antimicrobial approach that might lower the likelihood of antibiotic resistance. The engineered enzymes can also target specific bacterial species, according to the authors, thereby potentially reducing disruption of normal host microbiota.

For the full publication:

Reducing virulence of the human pathogen Burkholderia by altering the substrate specificity of the quorum-quenching acylase PvdQ.

By Gudrun Koch, Pol Nadal-Jimenez, Carlos R. Reis, Remco Muntendam, Marcel Bokhove, Elena Melillo, Bauke W. Dijkstra, Robbert H. Cool, and Wim J. Quax