Use of genetic and chemical synthetic lethality as probes of complexity in bacterial cell systems

Abstract

Different conditions and genomic contexts are known to have an impact on gene essentiality and interactions. Synthetic lethal interactions occur when a combination of perturbations, either genetic or chemical, result in a more profound fitness defect than expected based on the effect of each perturbation alone. Synthetic lethality in bacterial systems has long been studied; however, during the past decade, the emerging fields of genomics and chemical genomics have led to an increase in the scale and throughput of these studies. Here, we review the concepts of genomics and chemical genomics in the context of synthetic lethality and their revolutionary roles in uncovering novel biology such as the characterization of genes of unknown function and in antibacterial drug discovery. We provide an overview of the methodologies, examples and challenges of both genetic and chemical synthetic lethal screening platforms. Finally, we discuss how to apply genetic and chemical synthetic lethal approaches to rationalize the synergies of drugs, screen for new and improved antibacterial therapies and predict drug mechanism of action.