The Iron Content of Human Serum Albumin Modulates the Susceptibility of <i>Acinetobacter baumannii</i> to Cefiderocol
Jenny Escalante,
Brent Nishimura,
Marisel R. Tuttobene,
Tomás Subils,
Vyanka Mezcord,
Luis A. Actis,
Marcelo E. Tolmasky,
Robert A. Bonomo,
María Soledad Ramirez
Affiliations
Jenny Escalante
Center for Applied Biotechnology Studies, Department of Biological Science, College of Natural Sciences and Mathematics, California State University Fullerton, Fullerton, CA 92831, USA
Brent Nishimura
Center for Applied Biotechnology Studies, Department of Biological Science, College of Natural Sciences and Mathematics, California State University Fullerton, Fullerton, CA 92831, USA
Marisel R. Tuttobene
Área Biología Molecular, Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, Rosario S2000, Argentina
Tomás Subils
Instituto de Procesos Biotecnológicos y Químicos de Rosario (IPROBYQ, CONICET-UNR), Rosario S2000, Argentina
Vyanka Mezcord
Center for Applied Biotechnology Studies, Department of Biological Science, College of Natural Sciences and Mathematics, California State University Fullerton, Fullerton, CA 92831, USA
Luis A. Actis
Department of Microbiology, Miami University, Oxford, OH 45056, USA
Marcelo E. Tolmasky
Center for Applied Biotechnology Studies, Department of Biological Science, College of Natural Sciences and Mathematics, California State University Fullerton, Fullerton, CA 92831, USA
Robert A. Bonomo
Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Research Service and GRECC, Cleveland, OH 44106, USA
María Soledad Ramirez
Center for Applied Biotechnology Studies, Department of Biological Science, College of Natural Sciences and Mathematics, California State University Fullerton, Fullerton, CA 92831, USA
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 high-affinity 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.
