A requirement for Acinetobacter baumannii purine biosynthesis during lung infection is exacerbated by host zinc deficiency

TL;DR

This study shows that Acinetobacter baumannii needs to make purines to infect the lungs, and this need is worse when the host is zinc-deficient.

Contribution

The study identifies purine biosynthesis as a critical and zinc-sensitive pathway for A. baumannii lung infection.

Findings

A. baumannii purI mutants are less fit in the lungs of both zinc-sufficient and zinc-deficient mice.

Purine biosynthesis is more essential for A. baumannii in zinc-deficient hosts.

Purine biosynthesis is a potential drug target for treating A. baumannii lung infections.

Abstract

Acinetobacter baumannii is a leading cause of hospital-acquired infections, including ventilator-associated pneumonia. Dietary zinc deficiency is a major risk factor for pneumonia, and hospitalized patients at risk for A. baumannii infection have increased rates of zinc deficiency. We previously showed that dietary zinc deficiency enhanced A. baumannii pneumonia pathogenesis via an IL-13-dependent mechanism in mice. Here, we identified A. baumannii genes required for proliferation in the lungs of zinc-deficient mice using a genome-wide transposon sequencing (Tn-seq) screen. In zinc-deficient mice, Tn insertions in 614 A. baumannii genes led to significant differences in fitness in the lungs at 24 h. Most of these genes were also required in zinc-sufficient control mice. Mutants with disruptions in genes in the purine biosynthetic pathway, such as purI, and acinetobactin iron siderophore pathways were more strongly selected during lung infection in zinc-deficient mice compared to zinc-sufficient mice by Tn-seq. A reconstructed purI mutant was defective compared to wild type during lung infection in zinc-sufficient mice, with the defect further exacerbated in zinc-deficient mice. Thus, A. baumannii purine biosynthesis is required to infect the lung, and its requirement is exacerbated in a zinc-deficient host.

Dietary zinc deficiency is a major risk factor for infection worldwide. In the United States, hospitalized patients are at increased risk of zinc deficiency and A. baumannii pneumonia. In this study, A. baumannii purine biosynthesis was required for lung infection of mice, independent of dietary zinc. Therefore, bacterial purine biosynthesis is an attractive drug target for treating lung infections in patients with variable dietary zinc statuses, such as in hospitalized patients.

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