title: Peptide ligands in antibacterial drug discovery: use as inhibitors in target validation and target-based screening.
abstract: There is an urgent need to develop novel classes of antibiotics to counter the inexorable rise of resistant bacterial pathogens. Modern antibacterial drug discovery is focused on the identification and validation of novel protein targets that may have a suitable therapeutic index. In combination with assays for function, the advent of microbial genomics has been invaluable in identifying novel antibacterial drug targets. The major challenge in this field is the implementation of methods that validate protein targets leading to the discovery of new chemical entities. Ligand-directed drug discovery has the distinct advantage of having a concurrent analysis of both the importance of a target in the disease process and its amenability to functional modulation by small molecules. VITA is a process that enables a target-based paradigm by using peptide ligands for direct in vitro and in vivo validation of antibacterial targets and the implementation of high-throughput assays to identify novel inhibitory molecules. This process can establish sufficient levels of confidence indicating that the target is relevant to the disease process and inhibition of the target will lead to effective disease treatment.
authors.affiliation: Cubist Pharmaceuticals, Inc., 65 Hayden Avenue, Lexington, MA 02421, USA.
authors.forename: Kirsty A
authors.initials: KA
authors.lastname: Lapan
authors.forename: Joanne P
authors.initials: JP
authors.lastname: Chapple
authors.forename: Zoya
authors.initials: Z
authors.lastname: Galcheva-Gargova
authors.forename: Min
authors.initials: M
authors.lastname: Yang
authors.forename: Jianshi
authors.initials: J
authors.lastname: Tao
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000145:classification / Q000494:pharmacology* / Q000627:therapeutic use; D001424:Bacterial Infections / Q000188:drug therapy; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000302:isolation & purification; D016503:Drug Delivery Systems; D015195:Drug Design; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D004926:Escherichia coli / Q000187:drug effects / Q000235:genetics; D016680:Genome, Bacterial; D023281:Genomics; D006801:Humans; D008024:Ligands; D051379:Mice; D019151:Peptide Library; D010455:Peptides / Q000037:antagonists & inhibitors* / Q000302:isolation & purification; D011485:Protein Binding; D013329:Structure-Activity Relationship; D014162:Transfection
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D008024:Ligands; D019151:Peptide Library; D010455:Peptides