A large-scale chemical-genetic strategy to design antimicrobial combination chemotherapy for Mycobacterium tuberculosis

Abstract

The efficacies of all antibiotics against tuberculosis are eventually eroded by resistance. New strategies to discover drugs or drug combinations with higher barriers to resistance are needed. Previously, we reported the application of a large-scale chemical-genetic interaction screening strategy called PROSPECT to the discovery of new Mycobacterium tuberculosis inhibitors, which resulted in identification of the small molecule BRD-8000, an inhibitor of a novel target, EfpA. Leveraging the chemical genetic interaction profile of BRD-8000, we identified BRD-9327, another, structurally distinct small molecule EfpA inhibitor. We show that the two compounds are synergistic and display collateral sensitivity because of their distinct modes of action and resistance mechanisms. High-level resistance to one increases the sensitivity to and reduces the emergence of resistance to the other. Thus, the combination of BRD-9327 and BRD-8000 represents a proof-of-concept for the novel strategy of leveraging chemical-genetics in the design of antimicrobial combination chemotherapy in which mutual collateral sensitivity is exploited.\n\n\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=108 SRC=\"FIGDIR/small/772459v2_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (34K):\norg.highwire.dtl.DTLVardef@18da0eaorg.highwire.dtl.DTLVardef@13f76eforg.highwire.dtl.DTLVardef@1996766org.highwire.dtl.DTLVardef@5398ef_HPS_FORMAT_FIGEXP M_FIG C_FIG