Mechanisms of Metal Ion Homeostasis of Oral Streptococci

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ABSTRACT Zinc (Zn) is an essential trace metal to all forms of life that becomes toxic at high concentrations. Because it has both antimicrobial and anti-inflammatory properties, Zn is used as a therapeutic agent to treat a variety of infectious and non-infectious human conditions. While the efficacy of Zn as an anticaries agent is somewhat controversial, Zn salts are used in several oral healthcare products to prevent calculus formation, treat gingivitis and halitosis, and to control dental plaque accumulation. However, the consequences of rising salivary Zn levels above physiological concentrations to microbial and host-pathogen interactions are poorly understood and warrant further investigation. Recently, we discovered that S. mutans, a keystone pathogen in dental caries, is inherently more tolerant to the toxic effects of Zn than other streptococci, including commensal species associated with oral health. Using transcriptome and mutational analysis approaches, we identified a previously uncharacterized P1B-type ATPase exporter and cognate transcriptional factor, which we respectively named ZccE and ZccR, as primarily responsible for the remarkable high Zn tolerance of S. mutans. Searching public databases, we found that ZccE is unique to S. mutans providing an opportunity for the development of Zn-based antimicrobial therapies specifically tailored to eliminate S. mutans. Our working hypotheses are that the ability to overcome Zn toxicity is an important aspect of S. mutans pathophysiology, and that the identification of ZccE inhibitors can pave the way for the development of a species-specific Zn-based therapeutic modality. With the long-term goal of developing new anticaries therapies in mind, the specific goals of this conceptually, technically, and translationally innovative application are: (i) to uncover the regulatory mechanisms and pathways that mediate Zn tolerance in S. mutans; (ii) to determine the implications of increasing Zn concentrations, above physiological levels, to the composition and homeostasis of the oral microbiome; and (iii) to explore and then develop ZccE as an antimicrobial target. To accomplish these goals, the PI assembled a multidisciplinary team of investigators with complementary expertise in molecular microbiology and animal models (Abranches and Lemos), structured-based computer-aided drug design (Li), and medicinal chemistry (Huigens and Li). Completion of this study will: (i) significantly advance our understanding of the regulatory mechanisms and pathways that mediate bacterial Zn tolerance with the potential of revealing new therapeutic targets; (ii) shed light onto the implications and potential of Zn-based therapies in oral health and, more specifically, in caries control; and (iii) facilitate the rational design of new antimicrobial therapies to prevent/control the emergence of cariogenic biofilms.