Date of Award

31-8-2024

Document Type

Thesis

School

School of Chemical & Biotechnology

Programme

Ph.D.-Doctoral of Philosophy

First Advisor

Dr.Bhaskar Chandra Mohan Ramisetty

Keywords

Genome Plasticity, Bacterial Ecology, Horizontal Gene Transfer, Genetic Parasites, Agent-Based Model, Anti-Addiction Hypothesis, Antimicrobial Resistance

Abstract

Bacteria are constantly infected by obligate acellular genetic parasites, such as plasmids and phages. The genetic conflicts between bacteria and their parasites, aggravated by horizontal gene transfer, exert significant ecological and evolutionary pressure on their respective genomes. The eco-evolutionary significance of parasite-derived elements on bacterial genomes is not well understood.

This study explored the genomics of plasmid-derived genetic elements such as antimicrobial resistance genes (ARGs), type II endonuclease toxin-antitoxin systems (TAs) and endonuclease colicin-like bacteriocin (CLB) operons, and phage-derived prophages of Escherichia coli using bioinformatics and developing novel hybrid agent-based models. We sequenced eight E. coli isolated from local wastewater for comparative genomics with global wastewater isolates. The global analysis of wastewater E. coli genomes revealed alarmingly high averages of 80% resistant strain, 60% multidrug-resistant strains, and seven ARGs per genome.

Prophage genomics showed that, on average, each E. coli genome harbours seven prophage regions, most of which might be grounded and spread horizontally. Similarly, the plasmid-derived operons, CLB operons and TAs are widespread across the bacterial genera. CLB operons and TAs distribution exhibit a mutual exclusivity pattern: no identical CLB or TAs is encoded by both the plasmid and genome of a given bacterium. The mutual exclusivity pattern supports the anti-addiction hypothesis by which, CLB operons and TAs act as anti-addiction modules aiding in plasmid curing.

With the help of the hybrid agent-based models, we propose a theoretical model for the observed accumulation of parasite-derived elements in genomes. A common theme of coping with the parasite includes three major stages.

(i) Selection of the infected by parasite-induced advantage (by ARGs), addiction (by CLBs and TAs) or superinfection immunity (by prophages).

(ii) Emergence of host variants with chromosomal addiction modules (CLBs and TAs) aiding in plasmid curing, or ‘grounding’ of prophages thereby irreversibly abrogating the induction.

(iii) HGT of the parasite-derived elements across the population and gradual ordered degeneration over time.

Understanding the genetics of parasite-derived elements is important for managing the AMR problem and phage therapy against bacterial pathogens. Strategies like activation of TAs and CLBs or application of engineered prophages as obligate lytic agents hold promise for mitigating the HGT of mobile elements.

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