posted on 2019-11-28, 13:03authored byEachan
O. Johnson, Emma Office, Tomohiko Kawate, Marek Orzechowski, Deborah T. Hung
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 (PRimary screening
Of Strains to Prioritize Expanded Chemistry and Targets) for the discovery
of new Mycobacterium tuberculosis inhibitors, which
resulted in the identification of the small molecule BRD-8000, an
inhibitor of a novel target, EfpA [Johnson et al. (2019) Nature 517, 72]. 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.