PT  - JOURNAL ARTICLE
AU  - Eachan O. Johnson
AU  - Emma Office
AU  - Tomohiko Kawate
AU  - Marek Orzechowski
AU  - Deborah T. Hung
TI  - A large-scale chemical-genetic strategy to design antimicrobial combination chemotherapy for <em>Mycobacterium tuberculosis</em>
AID  - 10.1101/772459
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 772459
4099  - http://biorxiv.org/content/early/2019/09/27/772459.short
4100  - http://biorxiv.org/content/early/2019/09/27/772459.full
AB  - 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.