Antimicrobial and antibiofilm activities of halogenated phenols against Staphylococcus aureus and other microbes

Antimicrobial resistance is a global public health crisis that undermines the efficacy of treatments for infectious diseases, contributing to higher healthcare costs. Among Gram-positive bacteria, Staphylococcus aureus poses significant challenges due to its ability to develop resistance to multiple antibiotics, particularly in food and healthcare settings. Biofilm formation by S. aureus further enhances its resistance and pathogenicity. This study investigated the effects of 126 halogenated compounds on S. aureus biofilms, identifying five potent halogenated phenols. Among these, 2,4,6-triiodophenol (2,4,6-TIP) emerged as the most effective, exhibiting strong biofilm inhibition at a minimum inhibitory concentration (MIC) of 5 μg mL^-1. Additionally, 2,4,6-TIP demonstrated efficacy against biofilms formed by methicillin-resistant S. aureus MW2 and various Gram-negative bacteria, including Vibrio parahaemolyticus and uropathogenic Escherichia coli (UPEC), as well as the fungal species Candida albicans. It also prevented the formation of polymicrobial biofilms involving S. aureus and C. albicans. Beyond its antibiofilm properties, 2,4,6-TIP was effective in controlling key virulence factors in S. aureus, such as metabolic, hemolysis and protease activities. It also reduced swimming motility in V. parahaemolyticus and UPEC, and impaired hyphal formation in C. albicans. Transcriptomic analysis further revealed that 2,4,6-TIP significantly repressed the gene expression of RNAIII, a key regulator of biofilm and virulence production in S. aureus. Furthermore, in silico analysis, plant and nematode models showed that 2,4,6-TIP exhibited reduced toxicity compared to phenol. These findings unveiled the strong antimicrobial potential of 2,4,6-TIP and suggest a broad-spectrum capacity to target the virulent characteristics of medically important pathogens. It also highlights that strategic halogenation may play a critical role in enhancing the activity of phenolic compounds while alleviating their toxicity profiles. t.