title: Systems-level antimicrobial drug and drug synergy discovery.
abstract: Here, we review the 'target-centric' genomic strategy to antimicrobial discovery and share our perspective on identification, validation and prioritization of potential antimicrobial drug targets in the context of emerging chemical biology, genomics and phenotypic screening strategies. We propose that coupling the dual processes of antimicrobial small-molecule screening and target identification in a whole-cell context is essential to empirically annotate 'druggable' targets and advance early stage antimicrobial discovery. We also advocate a systems-level approach to annotating synthetic-lethal genetic interactions comprehensively within yeast and bacteria models. The resulting genetic interaction networks provide a landscape to rationally predict and exploit drug synergy between cognate inhibitors. We posit that synergistic combination agents provide an important and largely unexploited strategy to 'repurpose' existing chemical space and simultaneously address issues of potency, spectrum, toxicity and drug resistance in early stages of antimicrobial drug discovery.
authors.affiliation: Infectious Disease Research, Merck Research Laboratories, Kenilworth, New Jersey, USA. terry_roemer@merck.com
authors.forename: Terry
authors.initials: T
authors.lastname: Roemer
authors.forename: Charles
authors.initials: C
authors.lastname: Boone
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D000935:Antifungal Agents / Q000737:chemistry / Q000494:pharmacology*; D001419:Bacteria / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D055808:Drug Discovery; D004357:Drug Synergism; D023281:Genomics; D005838:Genotype; D057166:High-Throughput Screening Assays; D006801:Humans; D058990:Molecular Targeted Therapy; D010641:Phenotype; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology*; D054928:Validation Studies as Topic; D015003:Yeasts / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D000935:Antifungal Agents; D054852:Small Molecule Libraries