Prophage-encoded methyltransferase drives adaptation of community-acquired methicillin-resistant Staphylococcus aureus

Ulrich, R. J.; Podkowik, M.; Tierce, R.; Irnov, I.; Putzel, G.; Samhadaneh, N.; Lacey, K. A.; Boff, D.; Morales, S. M.; Makita, S.; Karagounis, T. K.; Zwack, E. E.; Zhou, C.; Kim, R.; Drlica, K.; Pironti, A.; van Bakel, H.; Torres, V. J.; Shopsin, B.

doi:10.1101/2024.04.17.589803

bioRxiv · 10.1101/2024.04.17.589803

Prophage-encoded methyltransferase drives adaptation of community-acquired methicillin-resistant Staphylococcus aureus

Ulrich, R. J.·Podkowik, M.·Tierce, R.·Irnov, I.·Putzel, G.·Samhadaneh, N.·Lacey, K. A.·Boff, D.·Morales, S. M.·Makita, S.·Karagounis, T. K.·Zwack, E. E.·Zhou, C.·Kim, R.·Drlica, K.·Pironti, A.·van Bakel, H.·Torres, V. J.·Shopsin, B.

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Abstract

We recently described the evolution of a community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) USA300 variant responsible for an outbreak of skin and soft tissue infections. Acquisition of a mosaic version of the {Phi}11 prophage (m{Phi}11) that increases skin abscess size was an early step in CA-MRSA adaptation that primed the successful spread of the clone. The present report shows how prophage m{Phi}11 exerts its effect on virulence for skin infection without encoding a known toxin or fitness genes. Abscess size and skin inflammation were associated with DNA methylase activity of an m{Phi}11-encoded adenine methyltransferase (designated pamA). pamA increased expression of fibronectin-binding protein A (fnbA; FnBPA), and inactivation of fnbA eliminated the effect of pamA on abscess virulence without affecting strains lacking pamA. Thus, fnbA is a pamA-specific virulence factor. Mechanistically, pamA was shown to promote biofilm formation in vivo in skin abscesses, a phenotype linked to FnBPAs role in biofilm formation. Collectively, these data reveal a novel mechanism--epigenetic regulation of staphylococcal gene expression--by which phage can regulate virulence to drive adaptive leaps by S. aureus. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=84 SRC="FIGDIR/small/589803v1_ufig1.gif" ALT="Figure 1"> View larger version (26K): org.highwire.dtl.DTLVardef@b97d6forg.highwire.dtl.DTLVardef@1da30f1org.highwire.dtl.DTLVardef@1c34311org.highwire.dtl.DTLVardef@6834df_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Ulrich, R. J., Podkowik, M., Tierce, R., Irnov, I., Putzel, G., Samhadaneh, N., Lacey, K. A., Boff, D., Morales, S. M., Makita, S., Karagounis, T. K., Zwack, E. E., Zhou, C., Kim, R., Drlica, K., Pironti, A., van Bakel, H., Torres, V. J., Shopsin, B.. 2024-04-17. Prophage-encoded methyltransferase drives adaptation of community-acquired methicillin-resistant Staphylococcus aureus. https://doi.org/10.1101/2024.04.17.589803

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