Biosynthesis and bioengineering of antibiotics in Burkholderia species

The emergence of antibiotic resistance combined with the decline in the discovery of novel antibiotic scaffolds has led to an urgent need for the development of effective antimicrobial treatments. Recently a Gram-negative genus of bacteria, Burkholderia, has been shown to be an untapped source of antimicrobial compounds. Two such compounds produced by Burkholderia are gladiolin and enacyloxin IIa (figure 1), which are active against the multidrug resistant pathogens Mycobacterium tuberculosis and Acinetobacter baumannii respectively. Both compounds are assembled by polyketide synthases, but there are parts of the biosynthesis of both natural products that are not well understood. Figure 1 The structures of gladiolin and enacyloxin IIa. The installation of the E,Z-diene motif in gladiolin (red, figure 1) was investigated using an intact protein MS-based assay with chemically synthesized polyketide intermediate mimics. The diene was shown to be installed by an unprecedented double dehydration, which appears to be conserved for the installation of dienes in some other polyketide natural products based on bioinformatics analyses. The biosynthesis of the dihydroxycyclohexanecarboxylic acid (DHCCA) unit of enacyloxin ... (continues)