Joint antibiotic and phage therapy: addressing the limitations of a seemingly ideal phage for treating<i>Staphylococcus aureus</i>infections

Abstract In response to increasing frequencies of antibiotic-resistant pathogens, there has been a resurrection of interest in the use of bacteriophage to treat bacterial infections: phage therapy. Here we explore the potential of a seemingly ideal phage, PYOSa, for combination phage and antibiotic treatment ofStaphylococcus aureusinfections. (i) This K-like phage has a broad host range; all 83 tested clinical isolates ofS.aureustested were susceptible to PYOSa. (ii) Because of the mode of action of PYOSaS. aureusis unlikely to generate classical receptor-site mutants resistant to PYOSa; none were observed in the 13 clinical isolates tested. (iii) PYOSakillsS. aureusat high rates. On the downside, the results of our experiments and tests of the joint action of PYOSaand antibiotics raise issues that must be addressed before PYOSais employed clinically. Despite the maintenance of the phage, PYOSadoes not clear the populations ofS. aureus. Due to the ascent of a phenotypically diverse array of small colony variants following an initial demise, the bacterial populations return to densities similar to that of phage-free controls. Using a combination of mathematical modeling andin vitroexperiments, we postulate and present evidence for a mechanism to account for the demise–resurrection dynamics of PYOSaandS. aureus. Critically for phage therapy, our experimental results suggest that treatment with PYOSafollowed by bactericidal antibiotics can clear populations ofS. aureusmore effectively than the antibiotics alone.Significance Statement The increasing frequency of antibiotic-resistant pathogens has fostered a quest for alternative means to treat bacterial infections. Prominent in this quest is a therapy that predates antibiotics: bacteriophage. This study explores the potential of a phage, PYOSa, for treatingStaphylococcus aureusinfections in combination with antibiotics. On first consideration, this phage, isolated from a commercial therapeutic cocktail, seems ideal for this purpose. The results of this population dynamic and genomic analysis study identify a potential liability of using PYOSafor therapy. Due to the production of potentially pathogenic atypical small colony variants, PYOSaalone cannot eliminateS. aureuspopulations. However, we demonstrate that by following the administration of PYOSawith bactericidal antibiotics, this limitation and potential liability can be addressed..

Medienart:

Preprint

Erscheinungsjahr:

2022

Erschienen:

2022

Enthalten in:

bioRxiv.org - (2022) vom: 22. Okt. Zur Gesamtaufnahme - year:2022

Sprache:

Englisch

Beteiligte Personen:

Berryhill, Brandon A. [VerfasserIn]
Huseby, Douglas L. [VerfasserIn]
McCall, Ingrid C. [VerfasserIn]
Hughes, Diarmaid [VerfasserIn]
Levin, Bruce R. [VerfasserIn]

Links:

Volltext [kostenfrei]

Themen:

570
Biology

doi:

10.1101/2020.04.24.060335

funding:

Förderinstitution / Projekttitel:

PPN (Katalog-ID):

XBI017748518