Antibiotic resistance alters the ability of Pseudomonas aeruginosa to invade bacteria from the respiratory microbiome

The emergence and spread of antibiotic resistance in bacterial pathogens is a global health threat. One important unanswered question is how antibiotic resistance influences the ability of a pathogen to invade the host-associated microbiome. Here we investigate how antibiotic resistance impacts the ability of a bacterial pathogen to invade bacteria from the microbiome, using the opportunistic bacterial pathogen Pseudomonas aeruginosa and the respiratory microbiome as our model system. We measure the ability of P. aeruginosa spontaneous antibiotic-resistant mutants to invade pre-established cultures of commensal respiratory microbes in an assay that allows us to link specific resistance mutations with changes in invasion ability. While commensal respiratory microbes tend to provide some degree of resistance to P. aeruginosa invasion, antibiotic resistance is a double-edged sword that can either help or hinder the ability of P. aeruginosa to invade. The directionality of this help or hindrance depends on both P. aeruginosa genotype and respiratory microbe identity. Specific resistance mutations in genes involved in multidrug efflux pump regulation are shown to facilitate the invasion of P. aeruginosa into Staphylococcus lugdunensis, yet impair invasion into Rothia mucilaginosa and Staphylococcus epidermidis. Streptococcus species provide the strongest resistance to P. aeruginosa invasion, and this is maintained regardless of antibiotic resistance genotype. Our study demonstrates how the cost of mutations that provide enhanced antibiotic resistance in P. aeruginosa can crucially depend on community context. We suggest that attempts to manipulate the microbiome should focus on promoting the growth of commensals that can increase the fitness costs associated with antibiotic resistance and provide robust inhibition of both wildtype and antibiotic-resistant pathogen strains. When bacterial pathogens become resistant to antibiotics, one clear outcome is that infections caused by these pathogens will be harder to treat with antibiotics. But is this the only consequence of antibiotic resistance? Here we asked how antibiotic resistance impacts the ability of a bacterial pathogen to interact with and invade communities of other bacteria present in the body (i.e., the microbiome). This question is important for understanding the potential of antibiotic-resistant pathogen strains to transmit between patients, and understanding when and how the microbiome may shape the spread of antibiotic resistance in bacterial pathogen populations. In this work, we carried out an experiment that allowed us to link specific antibiotic resistance mutations to changes in the ability of a bacterial pathogen to invade populations of different bacteria from the respiratory microbiome. We found that certain antibiotic resistance mutations could increase or decrease the ability of a bacterial pathogen to invade bacteria from the respiratory microbiome. The directionality of this depended on both the specific resistance mutations and the type of bacteria from the respiratory microbiome. Overall, this study highlights that the impact (e.g., cost or benefit) of antibiotic resistance mutations in bacterial pathogens is not uniform and can vary depending on the other bacteria there.