Staphylococcus epidermidis-Skin friend or foe?

Our skin is our first line of defense against environmental and pathogenic challenges. It is densely populated by a flora of bacteria, fungi, and viruses that normally interact with each other and with our immune system to promote skin health and homeostasis. Staphylococcus epidermidis is one of the most abundant bacterial colonizers of healthy human skin. While the field has historically assumed that all S. epidermidis isolates behave similarly, emerging evidence suggests that colonization by specific strains of S. epidermidis can either help or hurt the skin barrier depending on the context. In this short review, we discuss what is currently understood about S. epidermidis strain-level diversity and evaluate costs and benefits of S. epidermidis skin colonization. We challenge the current dogma that "all S. epidermidis strains behave equally" and posit that behavior is in fact highly context and strain dependent. Finally, in light of current proposals to use skin commensals as nonantibiotic treatments for acute or chronic skin diseases, we conclude that more work is urgently needed to fully understand the pathogenic and protective roles of commensals before we use them therapeutically.

Novel Peptide from Commensal Staphylococcus simulans Blocks Methicillin-Resistant Staphylococcus aureus Quorum Sensing and Protects Host Skin from Damage.

Recent studies highlight the abundance of commensal coagulase-negative staphylococci (CoNS) on healthy skin. Evidence suggests that CoNS actively shape the skin immunological and microbial milieu to resist colonization or infection by opportunistic pathogens, including methicillin-resistant Staphylococcus aureus (MRSA), in a variety of mechanisms collectively termed colonization resistance. One potential colonization resistance mechanism is the application of quorum sensing, also called the accessory gene regulator (agr) system, which is ubiquitous among staphylococci. Common and rare CoNS make autoinducing peptides (AIPs) that function as MRSA agr inhibitors, protecting the host from invasive infection. In a screen of CoNS spent media, we found that Staphylococcus simulans, a rare human skin colonizer and frequent livestock colonizer, released potent inhibitors of all classes of MRSA agr signaling. We identified three S. simulans agr classes and have shown intraspecies cross talk between noncognate S. simulans agr types for the first time. The S. simulans AIP-I structure was confirmed, and the novel AIP-II and AIP-III structures were solved via mass spectrometry. Synthetic S. simulans AIPs inhibited MRSA agr signaling with nanomolar potency. S. simulans in competition with MRSA reduced dermonecrotic and epicutaneous skin injury in murine models. The addition of synthetic AIP-I also effectively reduced MRSA dermonecrosis and epicutaneous skin injury in murine models. These results demonstrate potent anti-MRSA quorum sensing inhibition by a rare human skin commensal and suggest that cross talk between CoNS and MRSA may be important in maintaining healthy skin homeostasis and preventing MRSA skin damage during colonization or acute infection.

Castaneroxy A From the Leaves of Castanea sativa Inhibits Virulence in Staphylococcus aureus.

Methicillin-resistant Staphylococcus aureus (MRSA) represents one of the most serious infectious disease concerns worldwide, with the CDC labeling it a "serious threat" in 2019. The current arsenal of antibiotics works by targeting bacterial growth and survival, which exerts great selective pressure for the development of resistance. The development of novel anti-infectives that inhibit quorum sensing and thus virulence in MRSA has been recurrently proposed as a promising therapeutic approach. In a follow-up of a study examining the MRSA quorum sensing inhibitory activity of extracts of Italian plants used in local traditional medicine, 224C-F2 was reported as a bioactive fraction of a Castanea sativa (European chestnut) leaf extract. The fraction demonstrated high activity in vitro and effective attenuation of MRSA pathogenicity in a mouse model of skin infection. Through further bioassay-guided fractionation using reverse-phase high performance liquid chromatography, a novel hydroperoxy cycloartane triterpenoid, castaneroxy A (1), was isolated. Its structure was established by nuclear magnetic resonance, mass spectrometry and X-ray diffraction analyses. Isomers of 1 were also detected in an adjacent fraction. In a series of assays assessing inhibition of markers of MRSA virulence, 1 exerted activities in the low micromolar range. It inhibited agr::P3 activation (IC50 = 31.72 µM), δ-toxin production (IC50 = 31.72 µM in NRS385), supernatant cytotoxicity to HaCaT human keratinocytes (IC50 = 7.93 µM in NRS385), and rabbit erythrocyte hemolytic activity (IC50 = 7.93 µM in LAC). Compound 1 did not inhibit biofilm production, and at high concentrations it exerted cytotoxicity against human keratinocytes greater than that of 224C-F2. Finally, 1 reduced dermonecrosis in a murine model of MRSA infection. The results establish 1 as a promising antivirulence candidate for development against MRSA.

Triterpenoid acids isolated from Schinus terebinthifolia fruits reduce Staphylococcus aureus virulence and abate dermonecrosis.

Staphylococcus aureus relies on quorum sensing to exert virulence to establish and maintain infection. Prior research demonstrated the potent quorum sensing inhibition effects of "430D-F5", a refined extract derived from the fruits of Schinus terebinthifolia, a medicinal plant used for the traditional treatment of skin and soft tissue infections. We report the isolation and identification of three compounds from 430D-F5 that reduce virulence and abate dermonecrosis: 3-oxo-olean-12-en-28-oic acid (1), 3-oxotirucalla-7,24Z-dien-26-oic acid (2) and 3α-hydroxytirucalla-7,24 Z-dien-27-oic acid (3). Each compound inhibits all S. aureus accessory gene regulator (agr) alleles (IC50 2-70 µM). Dose-dependent responses were also observed in agr-regulated reporters for leucocidin A (lukA, IC50 0.4-25 µM) and glycerol ester hydrolase or lipase (gehB, IC50 1.5-25 µM). Surprisingly, dose-dependent activity against the nuclease reporter (nuc), which is under the control of the sae two-component system, was also observed (IC50 0.4-12.5 µM). Compounds 1-3 exhibited little to no effect on the agr-independent mgrA P2 reporter (a constitutive promoter from the mgrA two-component system) and the esxA reporter (under control of mgrA). Compounds 1-3 inhibited δ-toxin production in vitro and reduced dermonecrosis in a murine in vivo model. This is the first report of triterpenoid acids with potent anti-virulence effects against S. aureus.

Commensal Staphylococci Influence Staphylococcus aureus Skin Colonization and Disease.

Commensal organisms that constitute the skin microbiota play a pivotal role in the orchestration of cutaneous homeostasis and immune competence. This balance can be promptly offset by the expansion of the opportunistic pathogen Staphylococcus aureus, which is responsible for the majority of bacterial skin infections. S. aureus carriage is also known to be a precondition for its transmission and pathogenesis. Recent reports suggest that skin-dwelling coagulase-negative staphylococci (CoNS) can prime the skin immune system to limit the colonization potential of invaders, and they can directly compete through production of antimicrobial molecules or through signaling antagonism. We review recent advances in these CoNS colonization resistance mechanisms, which may serve to aid development of pharmacologic and probiotic intervention strategies to limit S. aureus skin colonization and disease.

XEN® Gel Stent in Medically Refractory Open-Angle Glaucoma: Results and Observations After One Year of Use in the United States.

INTRODUCTION: The purpose of this study was to evaluate intraocular pressure (IOP) lowering and safety of XEN® stent in medically refractory, progressive, open-angle glaucoma (OAG). METHODS: Forty-seven eyes of 42 patients were treated with XEN® stent alone or combined with phacoemulsification. RESULTS: Mean IOP decreased from 22.34 ± 7.34 mmHg to 12.91 ± 4.21, 12.95 ± 4.36, 13.49 ± 3.91, and 13.36 ± 3.63 mmHg at 1, 3, 6, and 12 months (95% confidence interval [CI] [20.24, 24.44], [11.71, 14.12], [11.63, 14.27], [12.36, 14.62], and [12.10, 14.62]), respectively. Mean number of medications decreased from 2.96 ± 1.20 (95% CI [2.62, 3.30]) at baseline to 0.75 ± 1.27 (95% CI [0.31, 1.19]) at 1 year. At 1 year (n = 32), complete success was achieved in 68.8% (n = 22/32) (i.e., IOP reduction ≥ 20% and IOP < 18 mmHg without medication or any secondary glaucoma intervention). Qualified success was achieved in 90.6% (n = 29/32) (i.e., IOP reduction of ≥ 20% and IOP < 18 mmHg with and without medication or any secondary glaucoma intervention). Eleven eyes had not yet reached 12 months. Two patients (three eyes) died before 1 year; one patient (one eye) was lost to follow up. Adverse events: localized choroidal hemorrhage in one eye; hypotony (IOP < 6 mmHg) at day 1 in 10 eyes, with full resolution by 2 weeks. No persistent hypotony or maculopathy occurred. Stent erosion with removal occurred in two eyes. Fourteen eyes (29.8%) underwent needling. One patient required trabeculectomy. CONCLUSIONS: XEN® stent is effective and relatively safe surgery for medically refractory, progressive, OAG out to 1 year. Intraocular pressure and medications were significantly reduced.