The rise of antibiotic resistance has researchers searching for new targets in pathogenic bacteria. One promising target is an enzyme called DXR that is essential for isoprenoid synthesis in most bacteria. DXR is inhibited by the antibiotic fosmidomycin, which is used to treat multidrug-resistant bacteria and the malaria parasite. However, a few pathogenic bacteria do not have DXR but have an unrelated enzyme called DRL instead.
In a recent Paper of the Week in The Journal of Biological Chemistry, a team led by Manuel Rodríguez-Concepción at the Centre for Research in Agricultural Genomics in Spain described the crystal structure of DRL from Brucella abortus, a bacterium that infects livestock. “Brucella strains usually infect cattle and other livestock but can also spread to humans,” which makes the bacterial strain a major and growing global public health threat, says Rodríguez-Concepción. He also points out that Brucella can be used as a biological weapon, making the search for highly specific antibiotics against these organisms critical.
The investigators found that DXR and DRL differed structurally despite catalyzing the same biochemical reaction. They also found that the active-site residues and the interactions with fosmidomycin between the two enzymes were different.
The investigators inferred that drugs could be designed specifically against one of the two enzymes, including DRL-specific inhibitors that function as narrow-range antibiotics. “The current availability of structural data of high quality makes this quite a feasible goal in a relatively short term,” says Rodríguez-Concepción, adding that his group’s next goal is to develop DRL-specific inhibitors that also function as efficient antibiotics.
- 1. Pérez-Gil, J. et al, J. Biol. Chem. doi:10.1074/jbc.M112.354811
Rajendrani Mukhopadhyay (firstname.lastname@example.org) is the senior science writer for ASBMB Today and the technical editor for The Journal of Biological Chemistry. Follow her on Twitter at www.twitter.com/rajmukhop.