Sulfur metabolic pathways are essential for the virulence and survival of human pathogens. In microbialcysteine biosynthesis, sulfonucleotide reductases (SRs) catalyze the reduction of 5'-phosphosulfoadenosine(APS) or 3'-phospho-5'phosphosulfoadenosine (PAPS) to sulfite using reducing equivalents from a proteincofactor, thioredoxin (Trx). In later stages, sulfite is further reduced to sulfide, which is used for the productionof essential sulfur-containing metabolites including cysteine, methionine, coenzymes, iron-sulfur clusters andantioxidants. SRs are excellent new targets for antibiotic development because of their critical role in bacterialsurvival and the lack of analogous enzymes in humans. This class of enzymes is particularly intriguing due tothe nature of the chemical reaction they catalyze. In addition, our preliminary results suggest that a highlyunusual iron-sulfur cluster in APS reductase may play an important catalytic role. However, many fundamentalquestions about their mechanism and structure remain unknown. Because the chemistry and biology ofbacterial SRs is not well understood, scientists have not been able to explore the potential of these enzymesas anti-infective targets. To this end, the broad goal of this project is directed towards obtaining detailedmechanistic and structural information on bacterial SRs, and on identifying small molecule inhibitors of SRs.The proposed research has three Specific Aims: (1) To elucidate the function of the [4Fe-4S] cluster in APSreductase, (2) To investigate large-scale conformational dynamics in the SR catalytic cycle, and (3) Todiscover SR inhibitors using library screening and virtual docking approaches. This work may lead to thedevelopment of antibiotics that can be used to combat drug-resistant bacteria, which would have a majorimpact on human health. Furthermore, we anticipate that these experiments will lead to important newfundamental insights into the (bio)chemistry of protein-associated iron-sulfur clusters and bacterial sulfurmetabolism.
Bacterial must assimilate sulfate from their environment in order to survive and initiate human infections. The discovery of methods to block this process could have a profound impact of public health. There is an urgent, global need for new antimicrobial therapies;the ability to interfere with bacterial virulence by intercepting sulfate metabolism represents a completely new therapeutic approach and is clinically timely.
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