Selective Antimicrobial Profiling of Crocatin A from Piper crocatum: A Potential Therapeutic Modulator for Caries-Driven Oral Dysbiosismple Abstract
Syifa Zahara Kultsum Azmi (a), Dikdik Kurnia (b), Toto Subroto (c)

Department of Chemistry, Faculty of Mathematics and Natural Sciences, Universitas Padjadjaran, Sumedang 45363, Indonesia

Abstract

Conventional caries management relies on broad-spectrum antimicrobials that indiscriminately disrupt oral eubiosis. This study investigates the targeted modulatory potential of Piper crocatum isolates against the keystone cariogenic pathogen Streptococcus mutans, while preserving the commensal Streptococcus salivarius subsp. thermophilus. Bioassay-guided fractionation of the methanolic leaf extract yielded a major active metabolite, structurally elucidated via comprehensive spectroscopic dereplication (UV, FTIR, MS, 1D/2D NMR) as the neolignan Crocatin A. In vitro ecological selectivity was assessed via differential disk diffusion, while molecular mechanisms were evaluated using thermodynamic in silico docking against pathogenic (GtfB, SpaP) and commensal (GspB, SrpA) receptors. In vitro, Crocatin A exhibited a distinct pathogen-selective therapeutic trajectory (Ecological Selectivity Index, SI 1.4), significantly outperforming the non-selective clinical standard, chlorhexidine (SI 0.97). In silico analyses revealed this selectivity is governed by high-affinity, enthalpy-driven binding to the pathogenic biofilm-forming enzyme GtfB (deltaG 6.5 kcal/mol and Ki 17.2 mM), anchored by specific hydrogen bonds (ARG638, LYS289). Conversely, interactions with commensal surface receptors were predominantly entropy-driven and transient, yielding theoretical inhibition constants 5.4 to 8.9, fold higher (Ki 93.2 to 154.6 mM) than the pathogen target. Ultimately, Crocatin A functions as a precision microbiome modulator. By selectively neutralizing S. mutans virulence pathways while preserving commensal viability, it facilitates colonization resistance, offering a paradigm shift from total oral sterilization to targeted eubiotic restoration.

Keywords: Crocatin A- Ecological selectivity- Glucosyltransferase B- Oral eubiosis- Piper crocatum

Topic: Biochemistry