Small Molecules Produced by Commensal Staphylococcus epidermidis Disrupt Formation of Biofilms by Staphylococcus aureus

Abstract

The microbiota influences host health through several mechanisms, including protecting it from pathogen colonization. <i>Staphylococcus epidermidis</i> is one of the most frequently found species in the skin microbiota, and its presence can limit the development of pathogens such as <i>Staphylococcus aureus</i><i>S. aureus</i> causes diverse types of infections ranging from skin abscesses to bloodstream infections. Given the increasing prevalence of <i>S. aureus</i> drug-resistant strains, it is imperative to search for new strategies for treatment and prevention. Thus, we investigated the activity of molecules produced by a commensal <i>S. epidermidis</i> isolate against <i>S. aureus</i> biofilms. We showed that molecules present in <i>S. epidermidis</i> cell-free conditioned media (CFCM) caused a significant reduction in biofilm formation in most <i>S. aureus</i> clinical isolates, including all 4 <i>agr</i> types and <i>agr</i>-defective strains, without any impact on growth. <i>S. epidermidis</i> molecules also disrupted established <i>S. aureus</i> biofilms and reduced the antibiotic concentration required to eliminate them. Preliminary characterization of the active compound showed that its activity is resistant to heat, protease inhibitors, trypsin, proteinase K, and sodium periodate treatments, suggesting that it is not proteinaceous. RNA sequencing revealed that <i>S. epidermidis</i>-secreted molecules modulate the expression of hundreds of <i>S. aureus</i> genes, some of which are associated with biofilm production. Biofilm formation is one of the main virulence factors of <i>S. aureus</i> and has been associated with chronic infections and antimicrobial resistance. Therefore, molecules that can counteract this virulence factor may be promising alternatives as novel therapeutic agents to control <i>S. aureus</i> infections.<b>IMPORTANCE</b><i>S. aureus</i> is a leading agent of infections worldwide, and its main virulence characteristic is the ability to produce biofilms on surfaces such as medical devices. Biofilms are known to confer increased resistance to antimicrobials and to the host immune responses, requiring aggressive antibiotic treatment and removal of the infected surface. Here, we investigated a new source of antibiofilm compounds, the skin microbiome. Specifically, we found that a commensal strain of <i>S. epidermidis</i> produces molecules with antibiofilm activity, leading to a significant decrease of <i>S. aureus</i> biofilm formation and to a reduction of previously established biofilms. The molecules potentiated the activity of antibiotics and affected the expression of hundreds of <i>S. aureus</i> genes, including those associated with biofilm formation. Our research highlights the search for compounds that can aid us in the fight against <i>S. aureus</i> infections.