Albany 2019: 20th Conversation - Abstracts

category image Albany 2019
Conversation 20
June 11-15 2019
Adenine Press (2019)

Identifying and targeting the Achilles heel of drug resistant bacteria

The emergence of drug resistant strains of M.tuberculosis poses a major threat to public health, warranting urgent attention to the problem of tackling antimicrobial resistance. A number of studies have sought to understand the causes of drug resistance, and have led to the identification of several mechanisms including mutations in key targets, upregulation of drug efflux pumps, etc. Yet, there is no understanding of which mechanisms are operative in a given condition, whether microbes explore multiple mechanisms simultaneously, or if such mechanisms are influenced by each other and lead to alterations in the cell in a synchronized manner. Towards this, an understanding of the global mechanisms leading to resistance becomes necessary. This in turn will provide a basis to develop novel therapeutic strategies for tackling drug resistance.

To address this, we adopt a systems level analysis of the biomolecular networks associated with the emergence or sustenance of drug-resistant phenotypes, from which we decipher cellular alterations in an unbiased manner and identify emergent vulnerabilities in resistant bacilli. We integrate genomic, transcriptomic and phenotypic data from the model system M.smegmatis and generate an integrated genome-scale response network, and employ network-mining approaches to identify the highest differential activities operative in the drug-resistant strain. The corresponding proteins are seen to form a well-connected orchestrated subnet, providing insights into newly emerged vulnerabilities in the resistant bacilli. The networks suggest that multiple mechanisms are at play simultaneously to overcome the drug stress, of which response to oxidative stress predominates. Through targeted screening we discover that the resistant bacilli exhibit collateral sensitivity to several compounds that block antioxidant responses. We then test the shortlisted compounds against M. tuberculosis and three different drug-resistant clinical isolates and study the mechanistic basis of the efficacies of these compounds. Three of the tested compounds were able to reverse resistance in mycobacteria. One of the identified compounds shows high promise as a key component of a re-purposable drug combination for treating drug-resistant tuberculosis.

Nagasuma Chandra

Indian institute of Science
Department of Biochemistry
Bangalore 560012, India

E-mail: nchandra@iisc.ac.in