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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. Staphylococcus epidermidis is one of the most frequently found species in the skin microbiota, and its presence can limit the development of pathogens such as Staphylococcus aureus S. aureus causes diverse types of infections ranging from skin abscesses to bloodstream infections. Given the increasing prevalence of S. aureus 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 S. epidermidis isolate against S. aureus biofilms. We showed that molecules present in S. epidermidis cell-free conditioned media (CFCM) caused a significant reduction in biofilm formation in most S. aureus clinical isolates, including all 4 agr types and agr-defective strains, without any impact on growth. S. epidermidis molecules also disrupted established S. aureus 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 S. epidermidis-secreted molecules modulate the expression of hundreds of S. aureus genes, some of which are associated with biofilm production. Biofilm formation is one of the main virulence factors of S. aureus 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 S. aureus infections.IMPORTANCE S. aureus 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 S. epidermidis produces molecules with antibiofilm activity, leading to a significant decrease of S. aureus biofilm formation and to a reduction of previously established biofilms. The molecules potentiated the activity of antibiotics and affected the expression of hundreds of S. aureus genes, including those associated with biofilm formation. Our research highlights the search for compounds that can aid us in the fight against S. aureus infections.

SUBMITTER: Glatthardt T

PROVIDER: S-EPMC7028967 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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

Glatthardt Thaís T Campos Juliana Curityba de Mello JCM Chamon Raiane Cardoso RC de Sá Coimbra Thiago Freitas TF Rocha Giulia de Almeida GA de Melo Marília Alves Figueira MAF Parente Thiago Estevam TE Lobo Leandro Araujo LA Antunes Luis Caetano Martha LCM Dos Santos Kátia Regina Netto KRN Ferreira Rosana Barreto Rocha RBR

Applied and environmental microbiology 20200218 5

The microbiota influences host health through several mechanisms, including protecting it from pathogen colonization. Staphylococcus epidermidis is one of the most frequently found species in the skin microbiota, and its presence can limit the development of pathogens such as Staphylococcus aureusS. aureus causes diverse types of infections ranging from skin abscesses to bloodstream infections. Given the increasing prevalence of S. aureus drug-resistant strains, it is ...[more]

PMID: 31862721

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Project description:Staphylococcus epidermidis is implicated in a multitude of human infections and is one of the major causes of clinical infections in hospitals, especially at surgical sites and on indwelling medical devices, such as orthopedic implants. These infections are especially dangerous because of the S. epidermidis propensity to form biofilms, which increases resistance to antibiotics and the natural immune response. This study investigated pulsed electromagnetic fields (PEMF) as a potential treatment to combat such infections, as PEMF exposure was expected to disrupt the electrostatic forces that adhere staphylococcal cells to surfaces and to one another. To test the effect of PEMF on biofilms, S. epidermidis cultures were exposed to PEMF at various durations either during the growth phase or after a full biofilm had formed. In addition, cells were exposed to PEMF and concomitant antibiotic treatment. Biofilm viability was quantified by both crystal violet and alamarBlue assays and scanning electron microscopy. The results demonstrated that PEMF significantly inhibited biofilm formation and disrupted preformed biofilms in vitro while also showing synergistic biofilm inhibition when combined with antibiotics. These combined results indicate that PEMF should be considered a promising novel technique for treating S. epidermidis biofilm infections and undergo further testing in vivo. IMPORTANCE Antibiotic resistance and biofilm infections are major issues in health care because of the lack of a successful treatment modality and poor patient outcomes. These infections are a particular issue following orthopedic surgery or trauma wherein an infection may form on an orthopedic implant or patient's bone. The presented study demonstrates that pulsed electromagnetic fields may be a promising novel treatment for such infections and can overcome the medical challenges presented by biofilm formation. Furthermore, the effects demonstrated are even greater when combining pulsed electromagnetic field therapy with traditional antibiotics.

Project description:In this paper, the metabolic activity in single and dual species biofilms of Staphylococcus epidermidis and Staphylococcus aureus isolates was investigated. Our results demonstrated that there was less metabolic activity in dual species biofilms compared to S. aureus biofilms. However, this was not observed if S. aureus and S. epidermidis were obtained from the same sample. The largest effect on metabolic activity was observed in biofilms of S. aureus Mu50 and S. epidermidis ET-024. A transcriptomic analysis of these dual species biofilms showed that urease genes and genes encoding proteins involved in metabolism were downregulated in comparison to monospecies biofilms. These results were subsequently confirmed by phenotypic assays. As metabolic activity is related to acid production, the pH in dual species biofilms was slightly higher compared to S. aureus Mu50 biofilms. Our results showed that S. epidermidis ET-024 in dual species biofilms inhibits metabolic activity of S. aureus Mu50, leading to less acid production. As a consequence, less urease activity is required to compensate for low pH. Importantly, this effect was biofilm-specific. Also S. aureus Mu50 genes encoding virulence-associated proteins (Spa, SplF and Dps) were upregulated in dual species biofilms compared to monospecies biofilms and using Caenorhabditis elegans infection assays, we demonstrated that more nematodes survived when co-infected with S. epidermidis ET-024 and S. aureus mutants lacking functional spa, splF or dps genes, compared to nematodes infected with S. epidermidis ET-024 and wild- type S. aureus. Finally, S. epidermidis ET-024 genes encoding resistance to oxacillin, erythromycin and tobramycin were upregulated in dual species biofilms and increased resistance was subsequently confirmed. Our data indicate that both species in dual species biofilms of S. epidermidis and S. aureus influence each other's behavior, but additional studies are required necessary to elucidate the exact mechanism(s) involved.

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

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

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