Researchers have uncovered new ways that bacteria respond to zinc—a metal that is used by the human immune system to target bacterial pathogens for destruction. Specifically, the researchers showed how a group of Streptococcus use a copper regulator to manage zinc intoxication, and they identified new genes involved in zinc resistance.

“This provides a new and fundamental understanding of how the pathogen carves a niche for itself in the human body,” said Kelvin Goh, PhD, a research fellow at Griffith University in Queensland, Australia, and one of the authors of the study, which was published in PLOS Pathogens (“Regulatory cross-talk supports resistance to Zn intoxication in Streptococcus”).

The work could pave the way for studies that design new strategies to treat bacterial infections without relying on antibiotics, which are rapidly becoming obsolete as resistance to them continues to rise.

The streptococci are a large group of bacteria, some of which are “good,” such as those found in yogurts, and some of which are “bad,” such as those that cause nasty and sometimes fatal infections in humans. The researchers focused on group B Streptococcus (GBS), which is usually harmless but can cause significant problems in the elderly or in those with chronic conditions such as diabetes.

Metals such as zinc play an important role in the body’s ability to protect against bacterial infection. The researchers examined how GBS responds to zinc exposure and identified a number of ways the bacterium is able to resist metal stress.

One of the ways the bacteria respond to zinc is by using a regulator for another metal—copper (Cu).

“We observed how a genetic switch in [GBS] that usually detects and respond to copper, also controls the bacterium’s responses to zinc, discovering a neat mechanism of ‘cross-talk’ in the biological response to these two very different metals,’’ said Matthew Sullivan, PhD, a senior research fellow at Griffith University and one of the authors on the study.

That “switch” is CopY. “RNAseq analysis of wild-type (WT) and copY-deficient GBS subjected to metal stress revealed unique transcriptional links between the systems for Cu and Zn detoxification,” the authors wrote. “We show that the Cu-sensing role of CopY extends beyond Cu and enables CopY to regulate Cu and Zn stress responses that effect changes in gene function for central cellular processes, including riboflavin synthesis. CopY also supported GBS intracellular survival in human macrophages and virulence during disseminated infection in mice.”

Goh added that the researchers also found “a raft of unknown cellular processes which help contribute to surviving zinc and copper stress in bacteria.”

“Identification of the Zn resistome of GBS using TraDIS revealed a suite of genes essential for GBS growth in metal stress,” they wrote. “Several of the genes identified are novel to systems that support bacterial survival in metal stress and represent a diverse set of mechanisms that underpin microbial metal homeostasis during cell stress.”

“Overall, this study shows that copY controls discrete systems for Cu and Zn homeostasis in Streptococcus and establishes a collection of novel genomic elements that enable the bacteria to survive Zn intoxication,” they concluded.

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