Abstract
AbstractProteolysis-targeting chimeras (PROTACs) represent a new therapeutic modality involving selectively directing disease-causing proteins for degradation through proteolytic systems. Our ability to exploit this targeted protein degradation (TPD) approach for antibiotic development remains nascent due to our limited understanding of which bacterial proteins will be labile TPD targets. Here, we use a genetic system to model chemically-induced proximity and degradation to screen essential proteins inMycobacterium smegmatis(Msm), a model for the major human pathogenM. tuberculosis(Mtb). We find that drug-induced proximity to the bacterial ClpC1P1P2 proteolytic complex is sufficient to degrade many, but not all, endogenousMsmproteins, profoundly inhibiting bacterial growth for some targets. We also show that TPD can potentiate the effects of existing antibiotics targeting the same pathways and complexes. Together, our results identify specific endogenous mycobacterial proteins as attractive targets for futureMtbPROTAC development, as both standalone antibiotics and potentiators of existing antibiotic efficacy.
Publisher
Cold Spring Harbor Laboratory