An Acinetobacter baumannii, Zinc-Regulated Peptidase Maintains Cell Wall Integrity during Immune-Mediated Nutrient Sequestration
Zachery R. Lonergan,
Brittany L. Nairn,
Jiefei Wang,
Yen-Pang Hsu,
Laura E. Hesse,
William N. Beavers,
Walter J. Chazin,
Jonathan C. Trinidad,
Michael S. VanNieuwenhze,
David P. Giedroc,
Eric P. Skaar
Affiliations
Zachery R. Lonergan
Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA; Microbe-Host Interactions Training Program, Vanderbilt University School of Medicine, Nashville, TN, USA
Brittany L. Nairn
Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA
Jiefei Wang
Department of Molecular and Cellular Biochemistry, Indiana University, Bloomington, IN, USA; Department of Chemistry, Indiana University, Bloomington, IN, USA
Yen-Pang Hsu
Department of Molecular and Cellular Biochemistry, Indiana University, Bloomington, IN, USA
Laura E. Hesse
Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA; Microbe-Host Interactions Training Program, Vanderbilt University School of Medicine, Nashville, TN, USA
William N. Beavers
Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA
Walter J. Chazin
Center for Structural Biology, Vanderbilt University School of Medicine, Nashville, TN, USA; Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN, USA; Department of Chemistry, Vanderbilt University, Nashville, TN, USA; Vanderbilt Institute for Infection, Immunology, and Inflammation, Vanderbilt University Medical Center, Nashville, TN, USA
Jonathan C. Trinidad
Department of Chemistry, Indiana University, Bloomington, IN, USA; Laboratory for Biological Mass Spectrometry, Department of Chemistry, Indiana University, Bloomington, IN, USA
Michael S. VanNieuwenhze
Department of Molecular and Cellular Biochemistry, Indiana University, Bloomington, IN, USA; Department of Chemistry, Indiana University, Bloomington, IN, USA
David P. Giedroc
Department of Molecular and Cellular Biochemistry, Indiana University, Bloomington, IN, USA; Department of Chemistry, Indiana University, Bloomington, IN, USA
Eric P. Skaar
Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA; Vanderbilt Institute for Infection, Immunology, and Inflammation, Vanderbilt University Medical Center, Nashville, TN, USA; Corresponding author
Summary: Acinetobacter baumannii is an important nosocomial pathogen capable of causing wound infections, pneumonia, and bacteremia. During infection, A. baumannii must acquire Zn to survive and colonize the host. Vertebrates have evolved mechanisms to sequester Zn from invading pathogens by a process termed nutritional immunity. One of the most upregulated genes during Zn starvation encodes a putative cell wall-modifying enzyme which we named ZrlA. We found that inactivation of zrlA diminished growth of A. baumannii during Zn starvation. Additionally, this mutant strain displays increased cell envelope permeability, decreased membrane barrier function, and aberrant peptidoglycan muropeptide abundances. This altered envelope increases antibiotic efficacy both in vitro and in an animal model of A. baumannii pneumonia. These results establish ZrlA as a crucial link between nutrient metal uptake and cell envelope homeostasis during A. baumannii pathogenesis, which could be targeted for therapeutic development. : Acinetobacter baumannii must acquire zinc during infection. During zinc starvation, A. baumannii expresses a peptidase named ZrlA. Lonergan et al. discovered ZrlA is required for bacterial cell envelope integrity and overcoming zinc limitation. Inactivation of zrlA increases bacterial membrane permeability, which improves antibiotic efficacy in vitro and during infection. Keywords: zinc, peptidase, calprotectin, Acinetobacter, peptidoglycan, metals, antibiotics, infection, nutritional immunity
