Insights into biofilm architecture and maturation enable improved clinical strategies for exopolysaccharide-targeting therapeutics

Author:

Temme,Joel

Tan, Zibin

Li,Mi

Yang,Mo

Wlodawer,Alexander

Huang, Xuefei

Schneekloth,Jay

Gildersleeve,Jeffrey
Author Address

Chemical Biology Laboratory, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA., Department of Chemistry, Michigan State University, 578 S Shaw Lane, East Lansing, MI 48824, USA; Institute for Quantitative Health Science and Engineering, Michigan State University, East Lansing, MI 48824, USA., Center for Structural Biology, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA; Basic Science Program, Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA., Center for Structural Biology, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA., Department of Chemistry, Michigan State University, 578 S Shaw Lane, East Lansing, MI 48824, USA; Institute for Quantitative Health Science and Engineering, Michigan State University, East Lansing, MI 48824, USA; Department of Biomedical Engineering, Michigan State University, East Lansing, MI 48824, USA., Chemical Biology Laboratory, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA. Electronic address: gildersj@mail.nih.gov.,

Abstract:

Polysaccharide intercellular adhesin (PIA), an exopolysaccharide composed of poly-N-acetyl glucosamine (PNAG), is an essential component in many pathogenic biofilms. Partial deacetylation of PNAG is required for biofilm formation, but limited structural knowledge hinders therapeutic development. Employing a new monoclonal antibody (TG10) that selectively binds highly deacetylated PNAG and an antibody (F598) in clinical trials that binds highly acetylated PNAG, we demonstrate that PIA within the biofilm contains distinct regions of highly acetylated and deacetylated exopolysaccharide, contrary to the previous model invoking stochastic deacetylation throughout the biofilm. This discovery led us to hypothesize that targeting both forms of PNAG would enhance efficacy. Remarkably, TG10 and F598 synergistically increased in vitro and in vivo activity, providing 90% survival in a lethal Staphylococcus aureus challenge murine model. Our advanced model deepens the conceptual understanding of PIA architecture and maturation and reveals improved design strategies for PIA-targeting therapeutics, vaccines, and diagnostic agents. Published by Elsevier Ltd.

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