Tailored Antibacterials and Innovative Laboratories for Phage (Φ) Research: Personalized Infectious Disease Medicine for the Most Vulnerable At-Risk Patients

Abstract

Mutation is the most powerful driver of change for life on Earth. Pathogenic bacteria utilize mutation as a means to survive strong live-die selective pressures generated by chemical antibiotics. As such, the traditional drug-making pipeline, characterized by significant financial and time investment, is insufficient to keep pace with the rapid evolution of bacterial resistance to structurally fixed and chemically unmalleable antibacterial compounds. In contrast, the genetic diversity and adaptive mutability of the bacteriophage can be leveraged to not only overcome resistance but also used for the development of enhanced traits that increase lytic potential and therapeutic efficacy in relevant host microenvironments. This is the fundamental premise behind Baylor College of Medicine's Tailored Antibacterials and Innovative Laboratories for Phage (F) Research (TAILFR) initiative. In this perspective, we outline the concept, structure, and process behind TAILFR's attempt to generate a personalized therapeutic phage that addresses the most clinically challenging of bacterial infections.

Targeting of Mammalian Glycans Enhances Phage Predation in the Gastrointestinal Tract

“…However, their greatest attribute has been speculated to be their abundance, estimated to be 10 31 on Planet Earth. The phage genosphere-the collection of all genes and their unique biology-is sometimes referred to as "viral dark matter" and may encode novel features that allow for enhanced lytic activity toward bacterial pathogens (24)(25)(26). Reasoning that this genosphere may include phage with unique phenotypes that facilitate lytic activity against pathobionts in mucosal environments, we report here a novel podovirus that binds human heparan sulfated proteoglycans and is effective at predation of its E. coli host in complex gastrointestinal (GI) microenvironments.…”

Screening for Lysogen Activity in Therapeutically Relevant Bacteriophages

“…[Background] The field of phage therapy, which is the clinical use of viruses to kill bacteria, has grown exponentially over recent decades (Gordillo Altamirano and Barr, 2019). Prior to their selection for therapeutic use, phages are typically subjected to a thorough characterization pipeline (Terwilliger et al, 2020). Lysogenic or temperate phages are those with the capacity to integrate themselves into their host's genome, and are routinely excluded from therapeutic use due to their subpar bactericidal ability, the emergence of homoimmunity, and the potentially harmful consequences of lysogenic conversion (Fortier and Sekulovic, 2013;Hyman, 2019).…”

Development of Phage Cocktails to Treat E. coli Catheter-Associated Urinary Tract Infection and Associated Biofilms

“…Phage have been successfully used to treat biofilm-associated infections recalcitrant to antibiotics ( Wright et al, 2009 ; Chan et al, 2018 ; Aslam et al, 2019 , 2020 ; Cano et al, 2020 ). Additionally, phage may self-dose ( Terwilliger et al, 2020 ), be evolved to re-target phage-resistant strains ( Salazar et al, 2021 ) and have features that enhance their activity in the complex microenvironments of the mammalian host, especially at mucosal surfaces ( Green et al, 2021 ). Our group previously characterized a library of phage that lyse multidrug-resistant extra-intestinal pathogenic E. coli strains ( Gibson et al, 2019 ).…”