We study the impact of bacterial behaviors on the evolution of AMR.
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The 'Why'
The 'Why'
👉 By 2050, antimicrobial resistance (AMR) is estimated to cause ~10 million global annual deaths†. As bacteria quickly develop genetic resistance, our arsenal of effective drugs is depleted. Unfortunately, none of the current antibiotic treatment regiments are directly aimed to delay the evolution of AMR.
👉 Majority of the AMR research to identify novel targets is performed on sensitive strains while bacterial isolates found in the clinic or farming industry are already resistant to antibiotics.
Our Recent Work
Our Recent Work
A major contributor to AMR evolution is the temporary survival behaviors of bacteria against antibiotics, enabling rapid genetic resistance acquisition, but the mechanisms of this temporary to genetic transition remain unclear. We recently discovered three such phenomena that accelerate the evolution of AMR: necrosignaling, phenotype surfing, and bacterial iron memory.
Overarching Goals of Our Research
Overarching Goals of Our Research
1. Understanding the molecular and evolutionary mechanisms of these temporary bacterial behaviors that accelerate AMR generation.
2. Identify genotypic and phenotypic vulnerabilities associated with AMR.
3. Identifying novel genetic targets and develop novel approaches to prevent or delay AMR by a combination of drugs that would i) kill bacteria and also ii) target the rate of AMR evolution.
Necrosignaling
Necrosignaling
Souvik discovered the phenomenon of 'Necrosignaling' in E. coli where a danger signal released from dead cells activated antibiotic survival pathways in live bacteria (Nature Communications, 2020).
The dead cells release a protein called AcrA from the periplasm that binds to the surface of live cells by interacting with an an outer membrane component of the RND efflux pump, TolC. This binding stimulate drug efflux and inducing expression of other efflux pumps to make bacteria resistant to several antibiotic classes.
This phenomenon exists in other Gram-negative and Gram-positive bacteria and displays species-specificity.
Efflux Accelerates AMR Evolution
Efflux Accelerates AMR Evolution
Efflux is a common mechanism of resistance to antibiotics. We showed that efflux itself accelerated AMR evolution. Cells with increased efflux exhibit a significant increase in the rate of AMR evolution. We uncovered a global regulatory network connecting high efflux to downregulation of specific DNA-repair pathways (Molecular Cell, 2022).
We found efflux inhibitors that could decrease the rate of AMR evolution.
We also showed how bacterial populations serve as a reservoir of AMR even in the absence of antibiotic selection pressure. High efflux at the edge of a population births mutants that, despite compromised fitness, survive there because of reduced competition. We called this phenomenon 'Phenotype Surfing'.
Iron Memory
Iron Memory
Swarming iron memory tracks from mother to daughters
Bacteria experience large environmental fluctuations to which they can readily adapt. In this study, using E. coli swarms as our experimental system, we asked: is there a heritable memory in bacteria?
We discovered that E. coli cells store memory in the form of cellular iron levels (PNAS, 2023).
This memory pre-exists in mother cells, is passed down to its fourth-generation daughter cells, and naturally lost by the seventh generation.
We also demonstrate that iron memory can integrate multiple stimuli, impacting other bacterial behaviors such as biofilm formation and antibiotic tolerance.
Motility Accelerates Evolution
Motility Accelerates Evolution
Flagella are highly complex rotary molecular machines that enable bacteria to not only migrate to optimal environments but to also promote range expansion, competitiveness, virulence, and antibiotic survival.
Flagellar motility is an energy-demanding process, where the sum of its production (biosynthesis) and operation (rotation) costs has been estimated to total ~10% of the entire energy budget of an Escherichia coli cell. The acquisition of such a costly adaptation process is expected to secure short-term benefits by increasing competitiveness and survival, as well as long-term evolutionary fitness gains.
We found that both production and operation costs of flagellar motility contribute to elevated mutation rates in bacteria.
Our findings suggest that flagellar movement may be an important player in tuning the rate of bacterial evolution (PNAS, 2024).
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