PROJECT SUMMARY In recent years, a massive increase in the rates of antibiotic resistant bacteria has been observed in clinical settings, causing significant concern from both the scientific community and government agencies. Among the pathogens causing these alarming infections is Acinetobacter baumannii, a microorganism that has developed resistance to almost all available antibiotics. Its extreme genome plasticity, largely facilitated by horizontal genetic transfer (HGT) processes, has contributed to its remarkable antibiotic-resistance phenotype. Transformation seems to be a particularly important HGT mechanism in this bacterium. However, the environmental signals triggering competence for natural transformation, the putative effectors involved in this process, and the molecular basis of this phenomenon are still poorly understood. Using the A. baumannii A118 clinical isolate as a model, the proposed project will examine the role of human host products as chemical inducers of DNA uptake. Considering our preliminary data, which show that different albumins cause a significant increase in the level of transformation frequency, this study will examine the role of Human Serum Albumin (HSA) and albumin-derived peptides in the development of bacterial competence and the uptake of foreign DNA (Aim 1). Moreover, we will determine the effects of HSA using a whole-genome transcriptional profiling approach in A118 (Aim 2). Through this last approach, we expect to identify genes and RNA regulators involved in natural transformation. This knowledge will provide critical insights into the molecular and cellular mechanism this pathogen uses to acquire resistance genes. Future studies can then use these findings to develop novel approaches to treat severe Acinetobacter human infections, particularly those caused by emerging multidrug-resistant isolates.