Editors' ChoiceDrug Discovery

Synthetic Lethality: Drug Repurposing with a Difference

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Science Translational Medicine  01 Oct 2014:
Vol. 6, Issue 256, pp. 256ec167
DOI: 10.1126/scitranslmed.3010415

β-Lactam is a core skeleton of several potent antibiotics, such as penicillins and carbapenems, that act by inhibiting cell-wall biosynthesis. Intriguingly, most β-lactams are ineffective against Mycobacterium tuberculosis (Mtb). In order to decipher the genetic determinants of this antibiotic resistance, Lun et al. used a screen, called gene-compound synthetic lethality (GCSL), which identified mutations in single genes that caused cell death in the presence of β-lactams (the compound). The authors screened a library of 2,921 mutants of Mtb against imipenem, a β-lactam antibiotic. Mutations in 74 Mtb genes displayed effective inhibition in presence of imipenem. These 74 genes belonged to several different pathways primarily associated with cell-wall biosynthesis. Lun et al. observed that mutant strains of Mtb selected from GCSL screens were more susceptible to imipenem than were wild-type strains. The authors then moved in vivo to determine if GCSL could identify genes relevant to β-lactam resistance during infection. Mice were infected with mutant or wild-type Mtb followed by treatment with imipenem. Similar to in vitro findings and, as predicted, the authors noted a greater decrease in bacterial lung burden in mice infected with mutant Mtb compared with wild-type bacteria, suggesting a lethal synergistic mechanism between gene and compound.

GCSL enabled identification of genes that conferred antibiotic resistance in Mtb, which in turn may be targeted in combination with the antibiotic for inducing the kill phenotype. As this study by Lun et al. suggests, it may be possible to screen other antibiotics that are not known to be effective on Mtb and repurpose them in combination with a gene mutant. Given that the scourge of multiple and extremely drug-resistant Mtb is on the rise, innovative technologies and methods like the GSCL reported here are needed to address the lack of antibiotics that are effective against such bacteria.

S. Lun et al. Synthetic lethality reveals mechanisms of Mycobacterium tuberculosis resistance to β-lactams, mBio 5, e01767-14 (2014). [Full Text]

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