Overcoming drug resistance by co-targeting

Abstract

Removal or suppression of key proteins in an essential pathway of a pathogen is expected to disrupt the pathway and prohibit the pathogen from performing a vital function. Thus disconnecting multiple essential pathways should disrupt the survival of a pathogen even when it has multiple pathways to drug resistance. We consider a scenario where the drug-resistance pathways are unknown. To disrupt these pathways, we consider a cut set S of G, where G is a connected simple graph representing the protein interaction network of the pathogen, so that G-S splits to two partitions such that the endpoints of each pathway are in different partitions. If the difference between the sizes of the two partitions is high, the probability of existence of a functioning pathway in one partition is increased. Thus, we need to partition the graph into two balanced partitions. We approximate the balanced bipartitioning problem with spectral bipartitioning since finding (2,1)-separator is NP-complete. We test our technique on E. coli and C. jejuni. We show that over 50% of genes in the cut sets are essential. Moreover, all proteins in the cut sets have fundamental roles in cell and inhibition of each of them is harmful for cell survival. Also, 20% and 17% of known targets are in the vertex cut of E. coli and C. jejuni. Hence our approach has produced plausible “co-targets” whose inhibition should counter a pathogen's drug resistance.