SELECTED PUBLICATIONS
​SEQUENCE VARIATION IN THE ACTIVE SITE OF MOBILE COLISTIN RESISTANCE PROTEINS IS EVOLUTIONARILY ACCOMMODATED THROUGH INTER-DOMAIN INTERACTIONS
A Joshi and N Matange - Biochem J, 2024
Our first foray into understanding colistin resistance and using Alphafold to make sense of structure-function relationships in proteins. Using extensive sequence mining we identify and chanracterise sequence variation at an active site residue among MCR (mobile colistin resistance) proteins. This sequence variation has consequences for the level of resistance that they confer to the last resort antibiotic, colistin. Our work led us to identify molecular mechanisms behind these phenotypes, specifically a role for inter-domain interactions in MCRs that alter mutational tolerances. We also show how evolutionary history and ancestry of MCRs is a major contributor of their current structure-function relationship.
Link to the paper below:
https://doi.org/10.1042/BCJ20240373
PERVASIVE GENE DEREGULATION UNDERLIES ADAPTATION AND MALADAPTATION IN TRIMETHOPRIM-RESISTANT E. COLI
R Vinchhi*, C Yelpure*, M Balachandran and N Matange - Mbio, 2023
* joint first authors
In this study we investigate how mutations in gene regulatory proteins produce domino-like deregulation across the gene regulatory network of bacteria. The result of these pervasive changes in gene expression on organismal fitness depends on the environmental context and drives subsequent evolution. This study has important implications for the evolution of negative feedback in two-component signalling systems in bacteria and in understanding how gene regulatory evolution can drive the evolution of antimicrobial resistance.
Link to the paper below:
https://doi.org/10.1128/mbio.02119-23
ADAPTIVE LABORATORY EVOLUTION OF ANTIMICROBIAL RESISTANCE IN BACTERIA FOR GENETIC AND PHENOTYPIC ANALYSES
R Vinchhi, C Jena and N Matange - STAR Protocols, 2023
In this publication, we have put together a detailed and comprehensive protocol for laboratory evolution of antimicrobial resistance. The protocol describes crucial conceptualisation, analyses and troubleshooting for lab evolution. Hopefully this will be a valuable resource for the community.
Link to the paper below:
https://www.sciencedirect.com/science/article/pii/S2666166722008851
ADAPTATION AND COMPENSATION IN A BACTERIAL GENE REGULATORY NETWORK EVOLVING UNDER ANTIBIOTIC SELECTION
V Patel and N Matange - eLife, 2021
How do gene regulatory networks evolve in response to drug challenge? In this study, we answer this question using laboratory evolution of trimethoprim in E. coli. We find that the 'first-hit' mutation is typically in the mgrB gene, a negative regulator of the virulence associated PhoPQ signalling pathway. This results in up-regulation of DHFR, the target of trimethoprim, conferring trimethoprim-tolerance. Subsequently, second and third-hit mutations sweep through the population to enhance fitness further. Most interestingly, the nature of these subsequent mutations is determined by how much drug bacteria face. Link to the paper below:
https://elifesciences.org/articles/70931
N Matange - Journal of Bacteriology, 2020
Are drug-resistant phenotypes dependent on antibiotic concentrations and genetic background? In my latest study I ask this question using trimethoprim resistance in E. coli as the model system. This work demonstrates how pleiotropic cellular substrates change the evolutionary advantage of a loss-of-function mutation in the Lon protease over a range of concentrations of trimethoprim. I also look at what the loss of Lon protease means for the spectrum of mutations within the DHFR enzyme that can confer trimethoprim resistance. Link to the paper below:
N Matange, S Hegde, S Bodkhe - Genetics, 2019
How does adaptation to antibiotics vary in environments with different drug pressures? An attempt to answer this question was recently published from my lab. We exposed a laboratory strain of E. coli to low and high levels of rifampicin and allowed them to evolve drug resistance. Counter-intuitively, bacteria that were exposed to the lowest drug pressure consistently evolved the highest drug MICs. This was due to an initial shift in lifestyle to pellicle-like which allowed the preferential enrichment of high-level resistant mutants subsequently. Life style changes, it appears, can modulate the evolutionary trajectories of bacterial populations. Link to the paper below:
N Matange, S Bodkhe, M Patel, P Shah - Biochemical Journal, 2018
This is the first of hopefully many publications from my lab at IISER. Here I show that drug resistance conferring mutations in bacterial dihydrofolate reductase enzymes may compromise stability of the protein. These trade-offs are therefore crucial in determining how resistance to trimethoprim evolves in bacteria. This work was done by me and a group of very hard-working Masters students from IISER-Pune and MSU-Baroda. Link below:
FROM MY PH.D. DAYS
During my Ph.D. I attempted to investigate the functions of cyclic nucleotide phosphodiesterases from Mycobacteria. Using biochemical and microbiological tools I showed that a M. tuberculosis-specific cAMP-phosphodiesterase moonlights as a modifier of cell wall permeability and may have several other cAMP-hydrolysis independent functions as well. I also spent some time thinking about phosphoesterases in general and how they may have been adapted to suit a variety of purposes throughout evolution. The interested reader can find published material from my Ph.D. work here:
http://www.ncbi.nlm.nih.gov/pubmed/?term=phosphodiesterase+matange
I have also dabbled in a number of interdisciplinary projects during my Ph.D. Some of these include using Raman Spectroscopy to understand carbon source-mediated changes in the metabolome of Mycobacteria, using Atomic Force Microscopy to understand the cell wall of Mycobacteria and using ChIP-seq and microarrays to understand the cAMP-regulon in Mycobacteria. Some of these results are published and the interested reader can find these materials here:
http://www.ncbi.nlm.nih.gov/pubmed/?term=raman+spectroscopy+matange