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

IF 6.6 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Cell Chemical Biology Pub Date : 2024-12-04 DOI:10.1016/j.chembiol.2024.11.005

J. Sebastian Temme, Zibin Tan, Mi Li, Mo Yang, Alexander Wlodawer, Xuefei Huang, John S. Schneekloth, Jeffrey C. Gildersleeve

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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.

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来源期刊

Cell Chemical Biology Biochemistry, Genetics and Molecular Biology-Molecular Medicine

CiteScore

14.70

自引率

2.30%

发文量

143

期刊介绍： Cell Chemical Biology, a Cell Press journal established in 1994 as Chemistry & Biology, focuses on publishing crucial advances in chemical biology research with broad appeal to our diverse community, spanning basic scientists to clinicians. Pioneering investigations at the chemistry-biology interface, the journal fosters collaboration between these disciplines. We encourage submissions providing significant conceptual advancements of broad interest across chemical, biological, clinical, and related fields. Particularly sought are articles utilizing chemical tools to perturb, visualize, and measure biological systems, offering unique insights into molecular mechanisms, disease biology, and therapeutics.