Abstract
Chronic (long-lasting) infections are globally a major and rising cause of morbidity and mortality. Unlike typical acute infections, chronic infections are ecologically diverse, characterized by the presence of a polymicrobial mix of opportunistic pathogens and human-associated commensals. To address the challenge of chronic infection microbiomes, we focus on a particularly well-characterized disease, cystic fibrosis (CF), where polymicrobial lung infections persist for decades despite frequent exposure to antibiotics. Epidemiological analyses point to conflicting results on the benefits of antibiotic treatment yet are confounded by the dependency of antibiotic exposures on prior pathogen presence, limiting their ability to draw causal inferences on the relationships between antibiotic exposure and pathogen dynamics. To address this limitation, we develop a synthetic infection microbiome model representing CF metacommunity diversity and benchmark on clinical data. We show that in the absence of antibiotics, replicate microbiome structures in a synthetic sputum medium are highly repeatable and dominated by oral commensals. In contrast, challenge with physiologically relevant antibiotic doses leads to substantial community perturbation characterized by multiple alternate pathogen-dominant states and enrichment of drug-resistant species. These results provide evidence that antibiotics can drive the expansion (via competitive release) of previously rare opportunistic pathogens and offer a path toward microbiome-informed conditional treatment strategies. IMPORTANCE We develop and clinically benchmark an experimental model of the cystic fibrosis (CF) lung infection microbiome to investigate the impacts of antibiotic exposures on chronic, polymicrobial infections. We show that a single experimental model defined by metacommunity data can partially recapitulate the diversity of individual microbiome states observed across a population of people with CF. In the absence of antibiotics, we see highly repeatable community structures, dominated by oral microbes. Under clinically relevant antibiotic exposures, we see diverse and frequently pathogen-dominated communities, and a nonevolutionary enrichment of antimicrobial resistance on the community scale, mediated by competitive release. The results highlight the potential importance of nonevolutionary (community-ecological) processes in driving the growing global crisis of increasing antibiotic resistance.