Host subversion of bacterial metallophore usage drives copper intoxication Original paper

Researched by:

  • Divine Aleru ID
    Divine Aleru

    User avatarI am a biochemist with a deep curiosity for the human microbiome and how it shapes human health, and I enjoy making microbiome science more accessible through research and writing. With 2 years experience in microbiome research, I have curated microbiome studies, analyzed microbial signatures, and now focus on interventions as a Microbiome Signatures and Interventions Research Coordinator.

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September 3, 2025

  • Metals
    Metals

    OverviewHeavy metals play a significant and multifaceted role in the pathogenicity of microbial species. Their involvement can be viewed from two primary perspectives: the toxicity of heavy metals to microbes and the exploitation of heavy metals by microbial pathogens to establish infections and evade the host immune response. Understanding these aspects is critical for both […]

  • Microbes
    Microbes

    Microbes, short for microorganisms, are tiny living organisms that are ubiquitous in the environment, including on and inside the human body. They play a crucial role in human health and disease, functioning within complex ecosystems in various parts of the body, such as the skin, mouth, gut, and respiratory tract. The human microbiome, which is […]

Researched by:

  • Divine Aleru ID
    Divine Aleru

    User avatarI am a biochemist with a deep curiosity for the human microbiome and how it shapes human health, and I enjoy making microbiome science more accessible through research and writing. With 2 years experience in microbiome research, I have curated microbiome studies, analyzed microbial signatures, and now focus on interventions as a Microbiome Signatures and Interventions Research Coordinator.

    Read More

Last Updated: 2025-09-03

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Divine Aleru

I am a biochemist with a deep curiosity for the human microbiome and how it shapes human health, and I enjoy making microbiome science more accessible through research and writing. With 2 years experience in microbiome research, I have curated microbiome studies, analyzed microbial signatures, and now focus on interventions as a Microbiome Signatures and Interventions Research Coordinator.

What was studied?

This original study tested how host subversion of bacterial metallophore usage changes metal stress during infection and showed that the host can flip staphylopine-based uptake in Staphylococcus aureus to drive copper intoxication under zinc-limited conditions. The authors asked whether zinc starvation, which induces the Cnt–staphylopine system, also opens an entry path for copper that then activates the copper stress response and hurts bacterial growth and fitness in vivo. They measured reporters for the copper efflux pump CopA, tracked intracellular metals, and compared wild-type and mutant strains that either rely on staphylopine for zinc (ΔadcA) or lack staphylopine import (ΔcntA). They also modeled host zinc withholding with calprotectin and tested competition in a mouse skin infection to link the in vitro signals to disease.

Who was studied?

Experiments used S. aureus Newman and USA300 LAC backgrounds with targeted deletions in adcA, cntA, cntKLM, and copA, plus combinations that forced reliance on either AdcABC or the Cnt–staphylopine system. The team exposed bacteria to zinc-limited media with graded copper, added calprotectin to mimic inflamed tissue, and then used inductively coupled plasma mass spectrometry to quantify intracellular copper and zinc. For in vivo relevance, they used female C57BL/6 mice in a subcutaneous abscess model and measured competitive indices for copA-deficient strains against controls, and for ΔadcA versus ΔcntA strains, to determine how metallophore use shapes copper stress during skin infection.

Most important findings

Zinc starvation switched staphylopine uptake in Staphylococcus aureus into a copper entry route that triggered strong copper stress at nanomolar levels. Loss of staphylopine import blocked this effect, while forcing staphylopine use increased copper sensitivity and intracellular copper. Deleting the copper pump CopA amplified damage and cut growth. Calprotectin, which starves zinc at inflamed sites, lowered the copper needed to induce stress. In a mouse skin abscess, strains lacking CopA or relying on staphylopine showed reduced fitness, proving that this copper import pathway operates in vivo. Similar risks may occur with yersiniabactin in Enterobacterales during inflammation.

Key implications

Clinicians can read zinc-starved, staphylopine-positive S. aureus as copper-sensitized in vivo. Embedding the cnt operon, copA/copBL, and calprotectin levels into a microbiome signatures database can flag niches where the host can exploit metallophore promiscuity. Copper-aware care might time or tune topical metals or adjuvants to amplify host copper stress while avoiding tissue harm. Genomic detection of yersiniabactin-like systems in Enterobacterales suggests broader reach of this rule. In simple terms, the host can turn a zinc-scavenging tool into a copper Trojan horse; mapping these modules helps risk-stratify skin, urinary, or gut infections and guides metal-aware stewardship.

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