Evaluating the potential efficacy and limitations of a phage for joint antibiotic and phage therapy of Staphylococcus aureus infections

• Type of Material: Article
• Authors: Brandon A Berryhill, Emory University; Douglas L Huseby, Uppsala University, Sweden; Ingrid C McCall, Emory University; Diarmaid Hughes, Uppsala University, Sweden; Bruce Levin, Emory University
• Language: English
• Date: 2021-03-09
• Publisher: PNAS
• Publication Version: Final Published Version
• Copyright Statement: © 2021 the Author(s). Published by PNAS.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1073/pnas.2008007118
• Title of Journal or Parent Work: Proceedings of the National Academy of Sciences of the United States of America
• Volume: 118
• Issue: 10
• Grant/Funding Information: Funds for this research were provided by grants from the US National Institutes of General Medical Sciences, R01 GM091875 and R35 GM 136407 (B.R.L.); Vetenskapsrådet (Swedish Research Council), 2017-0359; and the Scandinavian Society for Antimicrobial Chemotherapy, SLS-693211 and SLS-876451 (D.H.). These funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
• Keywords: Staphylococcal Infections; Staphylococcus aureus; population dynamics; Phage Therapy; Staphylococcus Phages; phage therapy; Anti-Bacterial Agents
• Research Categories: Biology, Microbiology; Chemistry, Biochemistry; Biology, General

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 of Staphylococcus aureus infections. This K-like phage has a broad host range; all 83 tested clinical isolates of S.aureus tested were susceptible to PYOSa. Because of the mode of action of PYOSa, S. aureus is unlikely to generate classical receptor-site mutants resistant to PYOSa; none were observed in the 13 clinical isolates tested. PYOSa kills S. aureus at high rates. On the downside, the results of our experiments and tests of the joint action of PYOSa and antibiotics raise issues that must be addressed before PYOSa is employed clinically. Despite the maintenance of the phage, PYOSa does not clear populations of S. aureus. Due to the ascent of a phenotyically 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 and in vitro experiments, we postulate and present evidence for a mechanism to account for the demise–resurrection dynamics of PYOSa and S. aureus. Critically for phage therapy, our experimental results suggest that treatment with PYOSa followed by bactericidal antibiotics can clear populations of S. aureus more effectively than the antibiotics alone.