The airways of cystic fibrosis (CF) patients have thick mucus, which fosters chronic, polymicrobial infections. and are two of the most prevalent respiratory pathogens in CF patients. In this study, we tested whether influences the susceptibility of to frontline antibiotics used to treat CF lung infections. Using our coculture model, we observed that addition of supernatants to biofilms grown either on epithelial cells or on plastic significantly decreased the susceptibility of to vancomycin. Mutant analyses showed that 2--heptyl-4-hydroxyquinoline -oxide (HQNO), a component of the quinolone signal (PQS) system, protects from the antimicrobial activity of vancomycin. Similarly, the siderophores pyoverdine and pyochelin also contribute to the ability of to protect from vancomycin, as did growth under anoxia. Under our experimental conditions, HQNO, supernatant, and growth under anoxia decreased growth, likely explaining why this cell wall-targeting antibiotic is less effective. supernatant did not confer additional protection to slow-growing small colony variants. Importantly, supernatant protects from other inhibitors of cell wall synthesis as well as protein synthesis-targeting antibiotics in an HQNO- and siderophore-dependent manner. We propose a model whereby causes to shift to fermentative growth when these organisms are grown in coculture, leading to reduction in growth and decreased susceptibility to antibiotics targeting cell wall and protein synthesis. Cystic fibrosis (CF) lung infections are chronic and difficult to eradicate. and are two of the most prevalent respiratory pathogens in CF patients and are associated with poor patient outcomes. Both organisms adopt a biofilm mode of growth, which contributes to high tolerance to antibiotic treatment and the recalcitrant nature of these infections. Here, we show that exoproducts decrease the sensitivity of biofilm and planktonic populations to vancomycin, a frontline antibiotic used to treat methicillin-resistant in CF patients. also protects from other cell wall-active antibiotics as well as various classes of protein synthesis inhibitors. Thus, interspecies interactions can have dramatic and unexpected consequences on antibiotic sensitivity. This study underscores the potential impact of interspecies interactions on antibiotic efficacy in the context of complex, polymicrobial infections.