Mechanistic Insights of Oligosaccharide Modulation at the Host-Pathogen Interface

Abstract

Human breast milk is the gold standard in infant nutrition. It supplies the developing neonate with nutrients, bioactive molecules, and microbes that confer total health to the infant. Human milk oligosaccharides (HMOs) are the third largest component of human breast milk and occur in high abundance. Originally discovered as a prebiotic factor in breast milk researchers have since demonstrated the vast health benefits these structurally diverse glycans confer. One such benefit of HMOs is their ability to modulate biofilm formation, a sophisticated bacterial behavior that contributes to pathogenicity and antimicrobial resistance. This work seeks to underscore the ways in which these behaviors are modified by HMOs. Here, using Acinetobacter baumannii, a gram-negative, highly threatening, multidrug resistant pathogen, we demonstrate the impressive ability of HMOs to not only prevent, but also dismantle, bacterial biofilms. We emphasized the applicability of these antiadhesive properties through an antibiotic adjuvant screen where HMOs significantly potentiated the efficacy of current antibiotics to this bacterium. This phenotype was perpetuated in a murine model of infection, where we showed significant reductions in bacterial colonization of respiratory organs when treated with HMOs in combination with an antibiotic compared to no treatment negative controls. Through a pan-omics approach we have identified phenylacetic acid (PAA), a ubiquitous microbial signaling molecule, as a key mediator of these HMO-induced perturbations. We report here that PAA modulates bacterial biofilm formation in a Csu independent manner, contrary to literature precedence. This work includes one of the first published accounts of HMO perturbations of a known bacterial signaling molecule. Further, we establish HMOs as a viable therapeutic intervention in the treatment of A. baumannii infections. Taken together, this work affords greater insight into HMO-modulation of bacterial behaviors as a mechanism to combat infectious diseases.