Revising the route to a stealthy siderophore

A surprising result has led UK scientists to revise the proposed biosynthetic route to petrobactin - a molecule needed by anthrax-causing bacteria to replicate. Greg Challis at the University of Warwick and colleagues say that their findings may ultimately lead to the development of new antibiotics for the disease.

Petrobactin - the stealth iron scavenger of Bacillus anthracis

Petrobactin is a siderophore - an iron scavenger - secreted by Bacillus anthracis to collect the iron it needs to reproduce. Called a stealth siderophore, it evades the molecule our immune system produces to capture it, contributing to the organism's virulence.
Challis's group has examined the role of the enzyme AsbB in petrobactin's biosynthesis. They first identified possible substrates for AsbB and obtained pure enzyme. Then, by treating the enzyme with different substrate combinations and finding which led to products and how quickly, the researchers showed that a previously proposed intermediate is unlikely to be significant in the pathway.
Challis says that he and his team were surprised and very excited by the findings, which led them to suggest a revised pathway to petrobactin. They had assumed, based on investigations of other siderophore biosynthetic pathways, that the route would be significantly different from the one they now propose.

"This could lead to inhibitors for petrobactin biosynthesis and therefore a potential treatment for anthrax"
- Greg Challis
'Our results provide the basic biochemical knowledge required to screen for inhibitors of AsbB,' says Challis. This could lead to inhibitors for petrobactin biosynthesis and therefore a potential treatment for anthrax, he adds.
The team's results also confirmed earlier computational predictions that enzymes such as AsbB use particular citrate derivatives as substrates, something that Christopher Schofield who investigates biosynthetic enzymes at the University of Oxford, UK, finds interesting. He says that the work 'provides more evidence for the value of chemical insights into bioinformatic analyses' and agrees that it could also one day help provide new antibacterials.
Challis and group member Daniel Oves-Costales were recently awarded a Biotechnology and Biological Sciences Research Council (BBSRC) grant to continue investigating the mechanisms of petrobactin biosynthesis and to search for inhibitors.
Frances Galvin

Link to journal articlePetrobactin biosynthesis: AsbB catalyzes condensation of spermidine with N8-citryl-spermidine and its N1-(3,4-dihydroxybenzoyl) derivative
Daniel Oves-Costales, Nadia Kadi, Mark J. Fogg, Lijiang Song, Keith S. Wilson and Gregory L. Challis, Chem. Commun., 2008
DOI: 10.1039/b809353a


19 August 2008
Chemical Biology