{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T16:52:42Z","timestamp":1790787162790,"version":"4.1.0"},"update-to":[{"DOI":"10.1371\/journal.ppat.1010477","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2022,8,18]],"date-time":"2022-08-18T00:00:00Z","timestamp":1660780800000}}],"reference-count":73,"publisher":"Public Library of Science (PLoS)","issue":"8","license":[{"start":{"date-parts":[[2022,8,8]],"date-time":"2022-08-08T00:00:00Z","timestamp":1659916800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH-NIDCR","award":["R01 DE019783"],"award-info":[{"award-number":["R01 DE019783"]}]},{"name":"NIH-NIDCR","award":["T90 DE021990"],"award-info":[{"award-number":["T90 DE021990"]}]}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p>\n                    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\n                    <jats:italic>Streptococcus mutans<\/jats:italic>\n                    , a keystone pathogen in dental caries and prevalent etiological agent of infective endocarditis, to overcome zinc toxicity are largely unknown. Here, we discovered that\n                    <jats:italic>S<\/jats:italic>\n                    .\n                    <jats:italic>mutans<\/jats:italic>\n                    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\n                    <jats:italic>S<\/jats:italic>\n                    .\n                    <jats:italic>mutans<\/jats:italic>\n                    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\n                    <jats:italic>S<\/jats:italic>\n                    .\n                    <jats:italic>mutans<\/jats:italic>\n                    . In addition to zinc, we found that ZccE, which was found to be unique to\n                    <jats:italic>S<\/jats:italic>\n                    .\n                    <jats:italic>mutans<\/jats:italic>\n                    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 \u0394\n                    <jats:italic>zccE<\/jats:italic>\n                    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\n                    <jats:italic>S<\/jats:italic>\n                    .\n                    <jats:italic>mutans<\/jats:italic>\n                    .\n                  <\/jats:p>","DOI":"10.1371\/journal.ppat.1010477","type":"journal-article","created":{"date-parts":[[2022,8,8]],"date-time":"2022-08-08T13:36:57Z","timestamp":1659965817000},"page":"e1010477","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":21,"title":["ZccE is a Novel P-type ATPase That Protects\u00a0Streptococcus mutans\u00a0Against Zinc Intoxication"],"prefix":"10.1371","volume":"18","author":[{"given":"Tridib","family":"Ganguly","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandra M.","family":"Peterson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marissa","family":"Burkholder","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica K.","family":"Kajfasz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacqueline","family":"Abranches","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0791-5863","authenticated-orcid":true,"given":"Jos\u00e9 A.","family":"Lemos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2022,8,8]]},"reference":[{"issue":"6","key":"ppat.1010477.ref001","doi-asserted-by":"crossref","first-page":"338","DOI":"10.1038\/nrmicro.2017.15","article-title":"Metal homeostasis and resistance in bacteria","volume":"15","author":"P Chandrangsu","year":"2017","journal-title":"Nat Rev Microbiol"},{"key":"ppat.1010477.ref002","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1146\/annurev-genet-120215-035146","article-title":"Transition Metals and Virulence in Bacteria","volume":"50","author":"LD Palmer","year":"2016","journal-title":"Annu Rev Genet"},{"key":"ppat.1010477.ref003","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.coi.2019.04.002","article-title":"Metals as phagocyte antimicrobial effectors","volume":"60","author":"JR Sheldon","year":"2019","journal-title":"Curr Opin 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