Attenuating the emergence of drug resistance by harnessing synthetic lethal interactions in a model organism

Drug resistance has emerged as a huge probem in many areas of medicine from cancer to infectious diseases. This is driving the development of novel therapeutic strategies. One that is gaining ground, is multi-target therapy, where combinations of drugs targeting different components of a disease network are deployed. A major impediment to this approach is the characterisation of sutiable targets for combination therapies. To date, most combinatorial therapy targets have been selected based on previous biological knowledge of drug mode of action and/or mechanisms of resistance, severely constraining the number of proteins that can be targeted.

Unbiased genome-wide screens will reveal many more components of the interaction networks of known drug targets, which could then be targeted in combination therapies. To test this principle in the context of antimicrobial resistance we have implemented an unbiased genome-wide screening technology, SGA analysis, facilitating characterisation of pair-wise synthetic genetic interactions. We performed an SGA screen with a Candida glabrata PDR1⁺ gain of function allele. PDR1 encodes a transcriptional regualtor and gain of function mutations in this gene, are the principal mediator of fluconazole resistance in C. glabrata. We identified a gcn5 null mutation as one negative synthetic interatin with PDR1⁺. We showed that deletion of GCN5 and/or chemical inhibition of the protein Gcn5, are snythetically lethal with PDR1⁺. These data demonstrate that deletion or chemcial inhibition of a PDR1⁺ synthetically lethal gene results in cellular death if wild-type PDR1 mutates to a PDR1⁺ FLZ resistance conferring allele.