The mortality rates of patients infected with Acinetobacter baumannii who were treated with cefiderocol (CFDC) were not as favorable as those receiving the best available treatment for pulmonary and bloodstream infections. Previous studies showed that the presence of human serum albumin (HSA) or HSA-containing fluids, such as human serum (HS) or human pleural fluid (HPF), in the growth medium is correlated with a decrease in the expression of genes associated with highaffinity siderophore-mediated iron uptake systems. These observations may explain the complexities of the observed clinical performance of CFDC in pulmonary and bloodstream infections, because ferric siderophore transporters enhance the penetration of CFDC into the bacterial cell. The removal of HSA from HS or HPF resulted in a reduction in the minimal inhibitory concentration (MIC) of CFDC. Concomitant with these results, an enhancement in the expression of TonB-dependent transporters known to play a crucial role in transporting iron was observed. In addition to inducing modifications in iron-uptake gene expression, the removal of HSA also decreased the expression of β-lactamases genes. Taken together, these observations suggest that environmental HSA has a role in the expression levels of select A. baumannii genes. Furthermore, the removal of iron from HSA had the same effect as the removal of HSA upon the expression of genes associated with iron uptake systems, also suggesting that at least one of the mechanisms by which HSA regulates the expression of certain genes is through acting as an iron source.Fil: Escalante, Jenny. California State University Fullerton. College of Natural Sciences and Mathematics. Center for Applied Biotechnology Studies. Department of Biological Science; United States.Fil: Nishimura, Brent. California State University Fullerton. College of Natural Sciences and Mathematics. Center for Applied Biotechnology Studies. Department of Biological Science; United States.Fil: Mezcord, Vyanka. California State University Fullerton. College of Natural Sciences and Mathematics. Center for Applied Biotechnology Studies. Department of Biological Science; United States.Fil: Tolmasky, Marcelo E.California State University Fullerton. College of Natural Sciences and Mathematics. Center for Applied Biotechnology Studies. Department of Biological Science; United States.Fil: Ramírez, María Soledad. California State University Fullerton. College of Natural Sciences and Mathematics. Center for Applied Biotechnology Studies. Department of Biological Science; United States.Fil: Tuttobene, Marisel Romina. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Área Biología Molecular; Argentina.Fil: Tuttobene, Marisel Romina. Instituto de Biología Molecular y Celular de Rosario (IBR-CONICET); Argentina.Fil: Subils, Tomás. Instituto de Procesos Biotecnológicos y Químicos de Rosario (IPROBYQ-CONICET); Argentina.Fil: Actis, Luis A. Miami University. Department of Microbiology; United States.Fil: Bonomo, Robert A. Research Service and GRECC Cleveland. Louis Stokes Cleveland Department of Veterans Affairs Medical Center; United States.Fil: Bonomo, Robert A. Case Western Reserve University School of Medicine. Departments of Medicine, Pharmacology, Molecular Biology and Microbiology, Biochemistry, Proteomics and Bioinformatics; United States.Fil: Bonomo, Robert A. CWRU-Cleveland VAMC Center for Antimicrobial Resistance and Epidemiology; United States.