Nishad Matange

Impeding pathways of intrinsic resistance in Escherichia coli confers antibiotic sensitization and resistance proofing Intrinsic resistance pathways in E. coli can be exploited to enhance antibiotic sensitivity and limit resistance evolution. This study shows that genetic inhibition of efflux pumps and cell envelope b...

Many thanks IISER Pune and DBT/Wellcome Trust India Alliance for generous support that allowed a study of this kind. Fantastic review process @plosbiology.org Highly recommended!

Here is the link to the paper again:

journals.plos.org/plosbiology/...

Bottomline: Our study highlights that targeting intrinsic resistance pathways, such as efflux, can be useful to ‘resistance proof’. Yet, the gap between genetic and pharmacological inhibition is likely to be a major challenge in the application of this approach as a therapeutic.

When we try to recapitulate these findings with pharmacological inhibition using an Efflux Pump Inhibitor (EPI), E. coli pulls out another trick from its bag of adaptive strategies. Its fixes mutations in transcriptional regulators to adapt to the EPI-Antibiotic combination.

We then use laboratory evolution of trimethoprim resistance to show that impeding efflux can also significantly compromise the ability to E. coli to adapt to antibiotic. This is mechanistically explained by the dampened benefit of adaptive mutations in efflux-deficient bacteria.

We then ask how effectively impeding two well known pathways, drug efflux through AcrAB-TolC and LPS biosynthesis, reduces the MIC of resistant strains. Efflux emerges as the clear winner from our data, across antibiotic and mutant combinations.

We start by screening the Keio mutant collection for single gene knockouts that are hypersensitive to trimethoprim and chloramphenicol. Both broad spectrum antimicrobials. We discover some new targets, in addition to re-discovering many usual suspects.

Impeding pathways of intrinsic resistance in Escherichia coli confers antibiotic sensitization and resistance proofing Intrinsic resistance pathways in E. coli can be exploited to enhance antibiotic sensitivity and limit resistance evolution. This study shows that genetic inhibition of efflux pumps and cell envelope b...

Out now at @plosbiology.org we evaluate the potential for antibiotic efflux and cell wall biogenesis as targets for reversing drug resistance and preventing its de novo evolution in Escherichia coli. Link below:

journals.plos.org/plosbiology/...