ZccE is a Novel P-type ATPase That Protects Streptococcus mutans Against Zinc Intoxication

• Published in: PLoS pathogens Vol. 18; no. 8; p. e1010477
• Main Authors: Ganguly, Tridib, Peterson, Alexandra M, Burkholder, Marissa, Kajfasz, Jessica K, Abranches, Jacqueline, Lemos, José A
• Format: Journal Article
• Language: English
• Published: San Francisco Public Library of Science 08.08.2022; Public Library of Science (PLoS)
• Subjects: Adenosine triphosphatase; Anti-inflammatory agents; Antiinfectives and antibacterials; Bacteria; Biology and Life Sciences; Cadmium; Chemical compounds; Chemical properties; Cobalt; Dental caries; Dental plaque; Endocarditis; Gingivitis; Health care; Homeostasis; Infections; Inflammation; Intoxication; Mammalian cells; Manganese; Medicine and Health Sciences; Metal ions; Metals; Off odor; Oral hygiene; Pathogens; Pharmacology; Physical Sciences; Physiological aspects; Pollution tolerance; Streptococcus; Streptococcus infections; Streptococcus mutans; Teeth; Toothpaste; Toxicity; Trace metals; Transcriptomes; Trends; Viral infections; Zinc; Zinc in the body; United States
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1010477

Zinc is a trace metal that is essential to all forms of life, but that becomes toxic at high concentrations. Because it has both antimicrobial and anti-inflammatory properties and low toxicity to mammalian cells, zinc has been used as a therapeutic agent for centuries to treat a variety of infectious and non-infectious conditions. While the usefulness of zinc-based therapies in caries prevention is controversial, zinc is incorporated into toothpaste and mouthwash formulations to prevent gingivitis and halitosis. Despite this widespread use of zinc in oral healthcare, the mechanisms that allow Streptococcus mutans , a keystone pathogen in dental caries and prevalent etiological agent of infective endocarditis, to overcome zinc toxicity are largely unknown. Here, we discovered that S . mutans is inherently more tolerant to high zinc stress than all other species of streptococci tested, including commensal streptococci associated with oral health. Using a transcriptome approach, we uncovered several potential strategies utilized by S . mutans to overcome zinc toxicity. Among them, we identified a previously uncharacterized P-type ATPase transporter and cognate transcriptional regulator, which we named ZccE and ZccR respectively, as responsible for the remarkable high zinc tolerance of S . mutans . In addition to zinc, we found that ZccE, which was found to be unique to S . mutans strains, mediates tolerance to at least three additional metal ions, namely cadmium, cobalt, and copper. Loss of the ability to maintain zinc homeostasis when exposed to high zinc stress severely disturbed zinc:manganese ratios, leading to heightened peroxide sensitivity that was alleviated by manganese supplementation. Finally, we showed that the ability of the Δ zccE strain to stably colonize the rat tooth surface after topical zinc treatment was significantly impaired, providing proof of concept that ZccE and ZccR are suitable targets for the development of antimicrobial therapies specifically tailored to kill S . mutans .