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Zinc-Enhanced Activity of an Antimicrobial Halogenated Phenazine Against Streptococcus mutans and Other Gram-positive

Jessica K Kajfasz1, Hannah B Hosay1, Qiwen Gao2

  • 1Department of Oral Biology, University of Florida College of Dentistry, Gainesville, FL, USA.

Biorxiv : the Preprint Server for Biology
|July 17, 2025
PubMed

Insights

Halogenated phenazine HP-29 effectively inhibits Gram-positive pathogens by disrupting metal ion regulation. Unexpectedly, zinc enhances HP-29

Area of Science:

  • Microbiology
  • Biochemistry
  • Antimicrobial Research

Background:

  • Halogenated phenazines (HP) show antimicrobial promise against Gram-positive pathogens, especially those in biofilms.
  • HP-29 is a potent HP compound effective against methicillin-resistant Staphylococcus aureus by causing iron starvation.
  • Maintaining trace metal homeostasis is crucial for bacterial survival, including oral pathogens like Streptococcus mutans.

Purpose of the Study:

  • To investigate the antimicrobial efficacy of HP-29 against Streptococcus mutans.
  • To determine the impact of metal supplementation on HP-29's activity.
  • To explore the potential of HP-29 as a dual-agent therapeutic strategy.

Main Methods:

  • Dose-dependent growth inhibition assays of S. mutans with HP-29.
  • Testing the effect of iron, cobalt, manganese, nickel, and zinc supplementation on HP-29 activity.
  • Inductively coupled plasma mass spectrometry (ICP-MS) to analyze intracellular metal content.
  • Transcriptome analysis to understand gene expression changes related to metal regulation.

Main Results:

  • HP-29 inhibited S. mutans growth in a dose-dependent manner.
  • Iron, cobalt, manganese, and nickel supplementation alleviated HP-29's inhibitory effect.
  • Zinc supplementation significantly enhanced HP-29's antimicrobial activity against S. mutans, Enterococcus faecalis, and S. aureus.
  • HP-29 exposure decreased intracellular iron and altered manganese and zinc levels, with zinc potentiation causing a 5-fold increase in intracellular zinc and a 50% reduction in manganese.
  • Transcriptome analysis revealed HP-29 disrupts genes involved in iron and manganese uptake and zinc efflux.

Conclusions:

  • HP-29 is a potent antimicrobial agent that broadly disrupts metal ion homeostasis in Gram-positive pathogens.
  • The synergistic effect of HP-29 with zinc presents a promising therapeutic strategy against Gram-positive pathogens.
  • HP-29's mechanism involves significant disruption of essential metal ion regulation, making it a versatile antimicrobial candidate.
Keywords:
S. mutansdental carieshalogenated phenazinetrace metalzinc

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