Genomic insights into bacteriophages: a new frontier in AMR detection and phage therapy

Abstract

The misuse and overprescription of antibiotics have accelerated the rise of antimicrobial resistance (AMR), rendering many antibiotics ineffective and leading to significant clinical challenges. The conventional treatment methods have become progressively challenging, posing a threat of evolving into an impending silent pandemic. The long track record of bacteriophages combating bacterial infections has renewed hope into the potential therapeutic benefits of bacteriophages. Bacteriophage therapy offers a promising alternative to antibiotics, particularly against multidrug-resistant (MDR) pathogens. This article explores the promise of phages as a potential means to combat superbugs from the perspective of the genomic and transcriptomic landscape of the phages and their bacterial host. Advances in bacteriophage genomics have expedited the detection of new phages and AMR genes, enhancing our understanding of phage-host interactions and enabling the identification of potential treatments for antibiotic-resistant bacteria. At the same time, holo-transcriptomic studies hold potential for discovering disease and context-specific transcriptionally active phages vis-à-vis disease severity. Holo-transcriptomic profiling can be applied to investigate the presence of AMR-bacteria, highlighting COVID-19 and Dengue diseases, in addition to the globally recognized ESKAPE pathogens. By simultaneously capturing phage, bacterial and host transcripts, this approach enables a better comprehension of the bacteriophage dynamics. Moreover, insight into these defence and counter-defence interactions is essential for augmenting the adoption of phage therapy at scale and advancing bacterial control in clinical settings.

Keywords: AMR; Holo-transcriptomics; bacteriophages; disease severity; genomics; phage therapy.

Figure 1

Summary of the experimental workflow and further downstream analysis. It starts with processing the sample to extract RNA, then converting it to DNA, preparing a library, and sequencing it. The data is then analyzed through various steps like checking quality, assembling the sequences, identifying viral genes, and predicting which host the virus infects. Different tools are used at each stage to help researchers better understand and classify the viruses. The figure was created using the licensed version of BioRender (https://www.biorender.com/).

Figure 2

Overview of the phage therapy steps, from screening and selecting specific bacteriophages through sequencing to clinical trials for treating AMR bacterial infections. This schematic outlines the key steps in phage therapy against MDR bacterial infections: (1) identification of antibiotic-resistant infection, (2) isolation of the pathogen, (3) in vitro screening of lytic phages from various sources, (4) genomic validation for safety and specificity, and (5) development and clinical evaluation of phage formulations for therapeutic use. The figure was created using the licensed version of BioRender (https://www.biorender.com/).

Figure 3

The effect of the interaction between a bacteriophage and its specific bacterial target on the human host. The phage population present in the human gut (phageome) helps to control the population of harmful bacteria by selectively targeting them and allowing the population of healthy bacteria to grow. Phageome elicits immune activation by internalising inside the human cell and activating the viral detection receptors and resulting in the production of inflammatory cytokines and activation of macrophages. Gut phageome can also reveal insights into the diversity in bacterial population by tracing the respective host organisms for gut bacteriophages. Bacteriophages also tend to coat bacteria for easier recognition by the immune system (opsonization), thereby enabling them to get phagocytosed. The figure was created using the licensed version of BioRender (https://www.biorender.com/).

Figure 4

Genomic advancements and potential for future phage research. Key areas of upcoming bacteriophage research revolve around the development of phage cocktails based on genomic profiling, synthetic biology approaches for engineering phages, analysis of receptor binding domains to study phage-host interaction, phage evolutionary dynamics, and diversity in the human microbiome, and to utilize advanced transcriptomic approaches. The figure was created using the licensed version of BioRender (https://www.biorender.com/).