title: Bacterial DNA replication enzymes as targets for antibacterial drug discovery.
abstract: BACKGROUND
  The bacterial replisome is composed of a large number of enzymes, which work in exquisite coordination to accomplish chromosomal replication. Effective inhibition inside the bacterial cell of any of the 'essential' enzymes of the DNA replication pathway should be detrimental to cell survival.
  
  
  METHODS
  This review covers DNA replication enzymes that have been shown to have a potential for delivering antibacterial compounds or drug candidates including: type II topoisomerases, a clinically validated target family, and DNA ligase, which has yielded inhibitors with in vivo efficacy. A few of the 'replisome' enzymes that are structurally and functionally well characterized and have been subjects of antibacterial discovery efforts are also discussed.
  
  
  CONCLUSIONS
  Identification of several essential genes in the bacterial replication pathway raised hopes that targeting these gene products would lead to novel antibacterials. However, none of these novel, single gene targets have delivered antibacterial drug candidates into clinical trials. This lack of productivity may be due to the target properties and inhibitor identification approaches employed. For DNA primase, DNA helicase and other replisome targets, with the exception of DNA ligase, the exploitation of structure for lead generation has not been tested to the same extent that it has for DNA gyrase. Utilization of structural information should be considered to augment HTS efforts and initiate fragment-based lead generation. The complex protein-protein interactions involved in regulation of replication may explain why biochemical approaches have been less productive for some replisome targets than more independently functioning targets such as DNA ligase or DNA gyrase.
authors.affiliation: Infection Innovative Medicines Unit, AstraZeneca R&D Boston, 35 Gatehouse Dr, Waltham, MA 02451, USA. Gautam.sanyal@astrazeneca.com
authors.forename: Gautam
authors.initials: G
authors.lastname: Sanyal
authors.forename: Peter
authors.initials: P
authors.lastname: Doig
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology; D001419:Bacteria / Q000187:drug effects* / Q000201:enzymology; D001665:Binding Sites; D004265:DNA Helicases / Q000037:antagonists & inhibitors; D011088:DNA Ligases / Q000037:antagonists & inhibitors; D019915:DNA Primase / Q000037:antagonists & inhibitors; D004261:DNA Replication / Q000187:drug effects*; D004269:DNA, Bacterial / Q000235:genetics; D055808:Drug Discovery / Q000379:methods*; D057166:High-Throughput Screening Assays; D006801:Humans; D019384:Nucleic Acid Synthesis Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D054730:Protein Interaction Domains and Motifs; D059005:Topoisomerase II Inhibitors; D059003:Topoisomerase Inhibitors / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D004269:DNA, Bacterial; D019384:Nucleic Acid Synthesis Inhibitors; D059005:Topoisomerase II Inhibitors; D059003:Topoisomerase Inhibitors; D019915:DNA Primase; D004265:DNA Helicases; D011088:DNA Ligases