# N-benzyl-N-methyldithiocarbamate (BMDC) combines with metals to produce antimicrobial and anti-biofilm activity against methicillin-resistant Staphylococcus aureus (MRSA) and Staphylococcus epidermidis

## TL;DR

A new compound, BMDC, combined with copper or zinc, effectively kills MRSA and prevents biofilm formation, offering a promising antimicrobial strategy.

## Contribution

BMDC-metal combinations show novel antimicrobial and anti-biofilm activity against MRSA and S. epidermidis.

## Key findings

- BMDC enhances copper uptake in bacteria, leading to 70-fold higher intracellular copper levels and bacterial death.
- Copper and zinc-BMDC combinations reduce biofilm formation and eradicate bacteria in established biofilms.
- Metal-BMDC combinations outperform vancomycin in biofilm disruption.

## Abstract

Methicillin-resistant Staphylococcus aureus (MRSA) is a high-priority microorganism that necessitates the development of new treatments, as it causes a substantial disease burden and economic impact globally. MRSA colonizes the skin and anterior nares and can potentially become invasive, leading to pneumonia and soft tissue infection. Additionally, MRSA can establish chronic infections in wounds and medical implants, partly due to its ability to form biofilms. Likewise, the skin commensal Staphylococcus epidermidis also causes similar infections, particularly through its ability to form a plastic-binding biofilm. In this study, we used N-benzyl-N-methyldithiocarbamate (BMDC) in combination with copper or zinc to decrease the viability of MRSA in both planktonic and biofilm settings in vitro, as well as to inhibit biofilm formation by S. epidermidis. We used Inductively Coupled Plasma Optical Emission Spectrometry (ICP-OES), biomass assessment, colony counts, and metabolism assays to interrogate the state of the bacterium after exposure to metal-BMDC. Furthermore, we compared these metal complexes to the antibiotic vancomycin, one of the current therapeutics used to treat MRSA infections. BMDC enhances copper uptake in bacteria, increasing intracellular copper levels by 70-fold compared to copper alone. Copper intoxication leads to a decrease in metabolic activity that ultimately results in bacterial death. Zinc also combines with BMDC, though likely through a different mechanism, and similarly exerts bactericidal effects. Significantly, both metal-BMDC combinations effectively reduce biofilm formation and eradicate bacteria within established biofilms in vitro, highlighting their potential as promising antimicrobial strategies against MRSA and S. epidermidis biofilms.

Antimicrobial-resistant bacteria, such as Staphylococcus aureus (MRSA) and Staphylococcus epidermidis, are a significant cause of morbidity and mortality in vulnerable populations, contributing to an escalating health and economic burden. Biofilms are an important reservoir that protects bacteria from immune clearance and antimicrobial agents. However, current strategies to effectively target MRSA biofilms are limited. This research describes a therapeutic approach that can disrupt biofilms in both MRSA and S. epidermidis, thereby enhancing bacterial clearance.