Microbiota-mediated colonization resistance to Acinetobacter baumannii.

PROJECT SUMMARY A healthy gut microbiota is a diverse microbial community that prevents colonization by invading pathogens, termed “colonization resistance.” Acinetobacter baumannii is a global public health threat due to its high rates of multidrug resistance and rapid spread in healthcare facilities by persistence in reservoirs including asymptomatic colonization of the gut. Asymptomatic gut colonization by A. baumannii dramatically increases the risk of clinical infection, emphasizing the potential impact on preventing A. baumannii infections by disrupting colonization. A. baumannii gut colonization is associated with antibiotic treatments, altered nutrition including tube feeding, illness, and hospitalization, suggesting there are multiple mechanisms to disrupt or bypass microbiota-mediated colonization resistance. We developed a post-antibiotics mouse model of A. baumannii gut colonization and determined that competition for nutrient niches is a major mechanism of microbiota-mediated colonization resistance. An emerging paradigm is that colonization resistance to invading microbes is conferred by occupation of all available nutrient niches by a complex microbiota that synergizes with phylogenetically-related “keystone species” that encode similar metabolic functions to the pathogen. However, A. baumannii metabolism fundamentally differs from the most closely related gut resident Gammaproteobacteria. Therefore, it is not known which gut resident microbes may serve as keystone species to synergize with a diverse microbiota to resist colonization to A. baumannii. We propose a model in which a complex resident microbiota competitively excludes A. baumannii from preferred nutrient niches, and A. baumannii overcomes microbiota-mediated colonization resistance by antibiotic disruption of the microbiota community or nutritional perturbations. Experiments in this proposal will identify keystone species that synergize with microbiota communities to confer colonization resistance, define nutrient niches from which A. baumannii is excluded by intact or disrupted microbiota, and determine whether nutritional perturbations that increase nutrient niches utilized by A. baumannii can overcome antibiotic resistance in the presence of an intact microbiota (without antibiotics). We expect completion of these experiments will provide conceptual advances to expand the paradigm of colonization resistance to invading opportunistic pathogens. Furthermore, the findings from this proposal will lay the foundation for development of new strategies and treatments to prevent A. baumannii colonization, disrupt spread, and prevent infections.