Pharmacological targeting of bacterial DNA ligase for treatment and prevention of bacterial infections

摘要

This invention provides methods for the discovery of molecules that target an essential step of bacterial DNA replication-the sealing of DNA strands by NAD+-dependent DNA ligase. Specific structural components of NAD+-dependent DNA ligase that are important for the reaction of DNA ligase with NAD+ and that comprise a putative binding site for the NMN component of NAD+ were identified. The invention also includes recombinant DNA ligase enzymes that are defective in their reaction with NAD+, but active in the ligation of pre-adenylated DNA nicks. An underlying principle of this invention is the use of NAD+-reactive and NAD+-defective ligases to identify molecules that specifically bind to the NAD+-binding site of DNA ligase and thereby interfere with the reaction of DNA ligase with NAD+.