Acinetobacter baumannii carbon metabolism during intermicrobial competition in the gut

PROJECT SUMMARY Acinetobacter baumannii is a critical public health threat due to its rapid spread in healthcare facilities and high rates of multidrug resistance. Asymptomatic colonization of the human gut is thought to be a major reservoir for A. baumannii in hospitals. Colonization by Acinetobacter spp. is associated with diet, antibiotics, illness, and hospitalization, all of which can be associated with gut microbiota dysbiosis. Asymptomatic colonization by A. baumannii is associated with increased risk of clinical infections, emphasizing the importance of colonization in A. baumannii pathogenesis. Therefore, it is critical to understand how A. baumannii colonizes the gut to develop new approaches to prevent A. baumannii spread. A major limitation to this approach is the lack of understanding of mechanisms A. baumannii uses to colonize and persist in the host gastrointestinal tract. Therefore, we developed a post-antibiotics mouse model to investigate strategies A. baumannii has evolved to colonize the gut. We discovered that ornithine catabolism is crucial for A. baumannii persistence in the gut and that ornithine catabolism is conserved in most A. baumannii strains. We further determine that ornithine is a non-preferred carbon source that A. baumannii utilizes when competitively excluded from preferred carbon sources by the resident microbiota. We identify transcriptional and post-transcriptional regulators that control genes required for ornithine catabolism. Dietary supplementation of ornithine or a preferred carbon source further promote A. baumannii gut colonization, demonstrating the potential for diet to affect A. baumannii colonization. Our central hypothesis is that A. baumannii senses nutrients in the gut environment to regulate carbon metabolism and compete with the resident gut microbiota by catabolizing ornithine. We will test this hypothesis by determining how A. baumannii integrates nutrient sensing to regulate ornithine catabolism and mechanisms of A. baumannii carbon source preference. We will further define how the microbiota and diet determine A. baumannii ornithine utilization in the gut using genetics, biochemistry, and mouse models. Finally, we will assess the role of ornithine catabolism in colonization and dissemination in clinical isolates from human gastrointestinal tract samples. These studies will identify how A. baumannii regulates carbon source utilization using ornithine catabolism as a model system. The results of these studies will lay the foundation to uncover the fundamental biology of metabolic strategies A. baumannii uses to compete for nutrients in the face of intermicrobial competition. Long-term, these findings will identify potential targets to eradicate A. baumannii from the gut reservoir and prevent healthcare outbreaks.