Dataset Information

Multi-metal Restriction by Calprotectin Impacts De Novo Flavin Biosynthesis in Acinetobacter baumannii.

ABSTRACT: Calprotectin (CP) inhibits bacterial viability through extracellular chelation of transition metals. However, how CP influences general metabolism remains largely unexplored. We show here that CP restricts bioavailable Zn and Fe to the pathogen Acinetobacter baumannii, inducing an extensive multi-metal perturbation of cellular physiology. Proteomics reveals severe metal starvation, and a strain lacking the candidate ZnII metallochaperone ZigA possesses altered cellular abundance of multiple essential Zn-dependent enzymes and enzymes in de novo flavin biosynthesis. The ?zigA strain exhibits decreased cellular flavin levels during metal starvation. Flavin mononucleotide provides regulation of this biosynthesis pathway, via a 3,4-dihydroxy-2-butanone 4-phosphate synthase (RibB) fusion protein, RibBX, and authentic RibB. We propose that RibBX ensures flavin sufficiency under CP-induced Fe limitation, allowing flavodoxins to substitute for Fe-ferredoxins as cell reductants. These studies elucidate adaptation to nutritional immunity and define an intersection between metallostasis and cellular metabolism in A. baumannii.

SUBMITTER: Wang J

PROVIDER: S-EPMC6525019 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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Publications

Multi-metal Restriction by Calprotectin Impacts De Novo Flavin Biosynthesis in Acinetobacter baumannii.

Wang Jiefei J Lonergan Zachery R ZR Gonzalez-Gutierrez Giovanni G Nairn Brittany L BL Maxwell Christina N CN Zhang Yixiang Y Andreini Claudia C Karty Jonathan A JA Chazin Walter J WJ Trinidad Jonathan C JC Skaar Eric P EP Giedroc David P DP

Cell chemical biology 20190321 5

Calprotectin (CP) inhibits bacterial viability through extracellular chelation of transition metals. However, how CP influences general metabolism remains largely unexplored. We show here that CP restricts bioavailable Zn and Fe to the pathogen Acinetobacter baumannii, inducing an extensive multi-metal perturbation of cellular physiology. Proteomics reveals severe metal starvation, and a strain lacking the candidate Zn<sup>II</sup> metallochaperone ZigA possesses altered cellular abundance of mu ...[more]

PMID: 30905682

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Project description:During infection, bacterial pathogens must adapt to a nutrient metal-limited environment that is imposed by the host. The innate immune protein calprotectin inhibits bacterial growth in vitro by chelating the divalent metal ions zinc (Zn2+, Zn) and manganese (Mn2+, Mn), but pathogenic bacteria are able to cause disease in the presence of this antimicrobial protein in vivo. One such pathogen is Acinetobacter baumannii, a Gram-negative bacterium that causes pneumonia and bloodstream infections that can be complicated by resistance to multiple antibiotics. A. baumannii inhibition by calprotectin is dependent on calprotectin Mn binding, but the mechanisms employed by A. baumannii to overcome Mn limitation have not been identified. This work demonstrates that A. baumannii coordinates transcription of an NRAMP family Mn transporter and a urea carboxylase to resist the antimicrobial activities of calprotectin. This NRAMP family transporter facilitates Mn accumulation and growth of A. baumannii in the presence of calprotectin. A. baumannii is found to utilize urea as a sole nitrogen source, and urea utilization requires the urea carboxylase encoded in an operon with the NRAMP family transporter. Moreover, urea carboxylase activity is essential for calprotectin resistance in A. baumannii Finally, evidence is provided that this system combats calprotectin in vivo, as deletion of the transporter impairs A. baumannii fitness in a mouse model of pneumonia, and this fitness defect is modulated by the presence of calprotectin. These findings reveal that A. baumannii has evolved mechanisms to subvert host-mediated metal sequestration and they uncover a connection between metal starvation and metabolic stress. IMPORTANCE:Acinetobacter baumannii is a bacterium that causes bloodstream, wound, urinary tract, and pneumonia infections, with a high disease burden in intensive care units. Treatment of A. baumannii infection is complicated by resistance to most antibiotics in use today, and resistance to last-resort therapies has become commonplace. New treatments for A. baumannii infection are desperately needed, but our current understanding of the bacterial factors required to cause infection is limited. We previously found that the abundant innate immune protein calprotectin inhibits the growth of A. baumannii by withholding essential metals. Despite this, A. baumannii is still able to infect wild-type mice, which produce calprotectin during infection. Here, we identify factors employed by A. baumannii during infection to overcome calprotectin-mediated metal sequestration. Moreover, we expose a connection between metal starvation and metabolism that may be a "chink in the armor" of A. baumannii and lead to new treatment options.

Dataset Information

Multi-metal Restriction by Calprotectin Impacts De Novo Flavin Biosynthesis in Acinetobacter baumannii.

Publications

Multi-metal Restriction by Calprotectin Impacts De Novo Flavin Biosynthesis in Acinetobacter baumannii.

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