[R03] Antistaphylococcal Phage Enhancement by Restriction Bypass and Dynamic Imaging
Ente: National Institute of Allergy and Infectious Diseases
Scadenza: 2028-04-30
Importo max: 77.500 EUR
Paese: US
Descrizione
Project Summary/Abstract
Staphylococcus aureus is the most common invasive human pathogen and a major contributor to
infection-related morbidity and mortality. Antibiotic resistance is often prevalent at baseline and can develop on
therapy. Further compounding the clinical challenge, even susceptible bacteria fail to respond appropriately to
first-line therapies in up to 30% of cases. In this context, antibiotic-bacteriophage combination therapies are
increasingly considered as potential adjunct or salvage therapies. Unfortunately, the host range of bacteriophage
can be limited by DNA restriction-modification systems that efficiently degrade “foreign” DNA, even originating
from other S. aureus bacteria. Custom testing of individual isolate-phage combinations is time and labor-
intensive, limiting the broad adoption of phage therapy. Additionally, an inability to trace phage particles in situ
results in persistent questions about dosing frequency, phage distribution to different body tissues and
penetration into infectious foci. Here we address these limitations through optimization of the phage propagation
strain. We add methylation specificity proteins to the propagation host to modify the daughter phage DNA. This
modified phage DNA is recognized as “self” by a wide variety of S. aureus bacteria, improving the daughter
phage host range without any permanent genetic changes to the phage. As an optional enhancement, the
propagation strain can make a component of phage capsids fluorescent, enabling tracking of daughter phage
for pharmacokinetic and pharmacodynamic studies. This should work for any phage propagated in the enhanced
propagation strain; however, subsequent generations infecting other bacteria will lose the fluorescent capsid. To
address this challenge, and enable studies including phage amplification in situ and phage penetration into
sequestered infection, we will modify the genome of a representative antistaphylococcal bacteriophage, Sb-1, to
express the fluorescent capsid regardless of the host strain. With these new tools we will increase the likelihood
of phage being able to infect a given isolate and enable visualization of bacteriophage for pharmacokinetic,
pharmacodynamic, and pre-clinical analysis.
Istituzione: WAYNE STATE UNIVERSITY
PI: Andrew David Berti
Progetto: 1R03AI199033-01
Settori: National Institute of Allergy and Infectious Diseases
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