An official website of the United States government
Abstract There is significant interest in approaches to the treatment of bacterial infections that block virulence without creating selective pressures that lead to resistance. Here, we report the development of an “anti‐virulence” strategy that exploits the activity of potent synthetic inhibitors of quorum sensing (QS) inStaphylococcus aureus. We identify peptide‐based inhibitors of QS that are resistant to sequestration or degradation by components of murine tissue and demonstrate that encapsulation of a lead inhibitor in degradable polymer microparticles provides materials that substantially inhibit QSin vitro. Using a murine abscess model, we show that this inhibitor attenuates methicillin‐resistantS. aureus(MRSA) skin infectionsin vivo, and that sustained release of the inhibitor from microparticles significantly improved outcomes compared to mice that received a single‐dose bolus. Our results present an effective and modular approach to controlling bacterial virulencein vivoand could advance the development of new strategies for skin infection control.
more »
« less
This content will become publicly available on September 2, 2026
Metabolites derived from bacterial isolates of the human skin microbiome inhibit Staphylococcus aureus biofilm formation
ABSTRACT The human skin microbiome is a diverse ecosystem that can help prevent infections by producing biomolecules and peptides that inhibit growth and virulence of bacterial pathogens.Staphylococcus aureusis a major human pathogen responsible for diseases that range from acute skin and soft tissue infections to life-threatening septicemia. Its ability to form biofilms is a key virulence factor contributing to its success as a pathogen as well as to its increased antimicrobial resistance. Here, we investigated the ability of bacterial skin commensals to produce molecules that inhibitS. aureusbiofilm formation. Matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) identified 77 human skin microbiome bacterial isolates fromStaphylococcusandBacillusgenera. Metabolites from cell-free concentrated media (CFCM) from 26 representative isolates were evaluated for their ability to inhibit biofilm formation by both methicillin-resistant (MRSA) and methicillin-sensitive (MSSA)S. aureusstrains. CFCM, derived from most of the isolates, inhibited biofilm formation to varying extents but did not inhibit planktonic growth ofS. aureus. Size fractionation of the CFCM of threeS.epidermidisisolates indicated that they produce different bioactive molecules. Cluster analysis, based on either MALDI-TOF mass spectra or whole-genome sequencing draft genomes, did not show clear clusters associated with levels of biofilm inhibition amongS. epidermidisstrains. Finally, similar biosynthetic gene clusters were detected in allS. epidermidisstrains analyzed. These findings indicate that several bacterial constituents of the human skin microbiome display antibiofilmin vitroactivity, warranting further investigation on their potential as novel therapeutic agents. IMPORTANCEThe skin is constantly exposed to the environment and consequently to numerous pathogens. The bacterial community that colonizes healthy skin is thought to play an important role in protecting us against infections.S. aureusis a leading cause of death worldwide and is frequently involved in several types of infections, including skin and soft tissue infections. Its ability to adhere to surfaces and produce biofilms is considered an important virulence factor. Here, we analyzed the activity of different species of bacteria isolated from healthy skin onS. aureusbiofilm formation. We found that some species ofStaphylococcusandBacilluscan reduceS. aureusbiofilm formation, although a generally lower level of inhibitory activity was observed compared toS. epidermidisisolates. AmongS. epidermidisisolates, strength of activity was dependent on the strain. Our data highlight the importance of mining the skin microbiome for isolates that could help combat skin pathogens.
more »
« less
- Award ID(s):
- 2320765
- PAR ID:
- 10639443
- Editor(s):
- Claesen, Jan
- Publisher / Repository:
- American Society for MIcrobiology
- Date Published:
- Journal Name:
- Microbiology Spectrum
- Volume:
- 13
- Issue:
- 9
- ISSN:
- 2165-0497
- Page Range / eLocation ID:
- 01306-25
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
More Like this
-
-
Abstract Drug‐resistant microorganisms cause serious problems in human healthcare, leading to the persistence in infections and poor treatment outcomes from conventional therapy. In this study, a gene‐targeting strategy using microbubble‐controlled nanoparticles is introduced that can effectively eliminate biofilms of methicillin‐resistantStaphylococcus aureus(MRSA) in vivo. Biofilm‐targeting nanoparticles (BTN) capable of delivering oligonucleotides are developed that effectively remove biofilm‐associated bacteria upon controlled delivery with diatom‐based microbubblers (MB). The activity of BTN in silencing key bacterial genes related to MRSA biofilm formation (icaA), bacterial growth (ftsZ), and antimicrobial resistance (mecA), as well as their multi‐targeting ability in vitro is validated. The integration of BTN with MB is next examined, resulting in synergistic effects in biofilm removal and antimicrobial activity in an ex vivo porcine skin model. The therapeutic efficacy is further investigated in vivo in a mouse wound model infected with MRSA biofilm, which showed that MB‐controlled BTN delivery substantially reduced bacterial load and led to the effective elimination of the biofilm. This study underscores the potential of the gene silencing platform with physical enhancement as a promising strategy to combat problems related to biofilms and antibiotic resistance.more » « less
-
Staphylococcus aureus are human facultative pathogenic bacteria and can be found as contaminants in the environment. The aim of our study was to determine whether methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-susceptible S. aureus (MSSA) isolated from coastal beach and river waters, anchialine pools, sand, and wastewater on the island of Hawaiʻi, Hawaiʻi, are a potential health risk. Samples were collected from three regions on Hawaiʻi Island from July to December 2020 during the COVID-19 pandemic and were characterized using whole-genome sequencing (WGS). From WGS data, multilocus sequence typing (MLST), SCCmec type, antimicrobial resistance genes, virulence factors, and plasmids were identified. Of the 361 samples, 98.1% were positive for Staphylococcus spp. and 7.2% were S. aureus positive (n = 26); nine MRSA and 27 MSSA strains were characterized; multiple isolates were chosen from the same sample in two sand and seven coastal beach water samples. The nine MRSA isolates were multi-drug resistant (6–9 genes) sequence type (ST) 8, clonal complex (CC) 8, SCCmec type IVa (USA300 clone), and were clonally related (0–16 SNP differences), and carried 16–19 virulence factors. The 27 MSSA isolates were grouped into eight CCs and 12 STs. Seventy-eight percent of the MSSA isolates carried 1–5 different antibiotic resistance genes and carried 5–19 virulence factors. We found S. aureus in coastal beach and river waters, anchialine pools, and sand at locations with limited human activity on the island of Hawaiʻi. This may be a public health hazard.more » « less
-
Staphylococcus aureus (S. aureus) is an asymptomatic colonizer of 30% of all human beings. While generally benign, antibiotic resistance contributes to the success of S. aureus as a human pathogen. Resistance is rapidly evolved through a wide portfolio of mechanisms including horizontal gene transfer and chromosomal mutation. In addition to traditional resistance mechanisms, a special feature of S. aureus pathogenesis is its ability to survive on both biotic and abiotic surfaces in the biofilm state. Due to this characteristic, S. aureus is a leading cause of human infection. Methicillin-resistant S. aureus (MRSA) in particular has emerged as a widespread cause of both community- and hospital-acquired infections. Currently, MRSA is responsible for 10-fold more infections than all multi-drug resistant (MDR) Gram-negative pathogens combined. Recently, MRSA was classified by the World Health Organization (WHO) as one of twelve priority pathogens that threaten human health. In this targeted mini-review, we discuss MRSA biofilm production, the relationship of biofilm production to antibiotic resistance, and front-line techniques to defeat the biofilm-resistance system.more » « less
-
null (Ed.)Staphylococcus aureus infections are of growing concern given the increased incidence of antibiotic resistant strains. Egypt, like several other countries, has seen alarming increases in methicillin-resistant S. aureus (MRSA) infections. This species can rapidly acquire genes associated with resistance, as well as virulence factors, through mobile genetic elements, including phages. Recently, we sequenced 56 S. aureus genomes from Alexandria Main University Hospital in Alexandria, Egypt, complementing 17 S. aureus genomes publicly available from other sites in Egypt. In the current study, we found that the majority (73.6%) of these strains contain intact prophages, including Biseptimaviruses, Phietaviruses, and Triaviruses. Further investigation of these prophages revealed evidence of horizontal exchange of the integrase for two of the prophages. These Egyptian S. aureus prophages are predicted to encode numerous virulence factors, including genes associated with immune evasion and toxins, including the Panton–Valentine leukocidin (PVL)-associated genes lukF-PV/lukS-PV. Thus, prophages are likely to be a major contributor to the virulence of S. aureus strains in circulation in Egypt.more » « less
