Chemical genetics in drug discovery

Abstract

Chemical-genetic approaches are based on measuring the cellular outcome of combining genetic and chemical perturbations in large-numbers in tandem. In these approaches the contribution of every gene to the fitness of an organism is measured upon exposure to different chemicals. Current technological advances enable the application of chemical genetics to almost any organism and at an unprecedented throughput. Here we review the underlying concepts behind chemical genetics, present its different vignettes and illustrate how such approaches can propel drug discovery.

Chemical-genetic profiling reveals cross-resistance and collateral sensitivity between antimicrobial peptides

“…It has recently been proposed that chemical-genetics could be employed to infer whether resistance evolution to an antimicrobial agent would lead to cross-resistance to another agent 12 . In particular, a high overlap in the latent resistomes may indicate the emergence of cross-resistance during evolution in nature or in the laboratory.…”

“…Chemical-genetic profiling is a reverse genetic approach that quantifies the susceptibility of a genome-wide collection of mutant libraries to a set of chemical compounds 12 . By modulating gene dosage (i.e.…”

“…those with a large overlap between the gene sets influencing resistance to them, are likely to share cellular targets and mechanism of action 16 . Therefore, chemical-genetics has been proposed as a useful tool to infer if resistance evolution to an antibiotic would lead to cross-resistance (decreased sensitivity) or collateral sensitivity (increased sensitivity) to another antibiotic 12,19 .…”

Machine learning and image-based profiling in drug discovery

“…For example, annotated libraries of pharmacologically active small molecules could be profiled to hypothesize off-targets and to suggest drug-target pairs with possibilities for repurposing ∗∗25 , 30 . Chemical genetics approaches also allow a systematic survey for drug repurposing by linking the effect of small molecules with the absence or presence of loss- or gain-of-function alleles ∗∗25 , 31 . Further strategies include the association of small molecules to a new target by comparing its induced phenotype to that of a reference molecule and the unbiased testing of small molecules for candidates that reverse a disease-associated cellular phenotype to the wild-type phenotype ∗∗25 , 30 , 32 .…”

“…In such screens, libraries of loss-of-function or gain-of-function mutant strains were screened against chemical libraries to measure genotype-dependent changes in fitness. Comparisons of phenotypic responses of mutant strains across chemical perturbations allowed to map genes with shared function and, by assessing the response across a panel of mutants, the bioactivity and cellular targets of small molecules [31] .…”