The Burkholderia cepacia complex (Bcc) is a group of closely related Gram-negative bacteria. Members of this group are known for their many beneficial agricultural applications, but also as pathogens that cause devastating lung infections in patients with cystic fibrosis (CF). All Bcc strains are highly resistant to most antibiotics and they quickly predominate over other bacteria once they infect the lungs of CF patients, suggesting they may themselves produce antibiotics that kill competitors.
In collaboration with Prof. Eshwar Mahenthiralingam at the University of Cardiff, screening a large collection of Bcc strains has identified strong activities produced by Burkholderia ambifaria against multidrug-resistant pathogens, in particular against the Burkholderia dolosa, which is known to cause chronic infections in CF patients that are associated with accelerated loss of lung function and decreased survival. A novel and unusual B. ambifaria anti-Gram-negative activity was linked to the production of the known antibiotic enacyloxin IIa and its novel derivative iso-enacyloxin IIa (Figure), products of a cryptic polyketide biosynthetic gene cluster.
The above findings suggest that enacyloxin IIa may be a promising lead for the development of novel antibiotics to tackle potentially life-threating B. dolosa infections in CF sufferers. Currently we are developing an approach to the production of enacyloxin IIa analogues for structure-activity relationship (SAR), metabolism and toxicity studies that leverages our insight into the biosynthesis of this metabolite and subsequent unpublished biochemical investigations.