Staphylococcus aureus is a major human pathogen that causes a wide range of clinical infections. It is a leading cause of bacteremia and infective endocarditis as well as osteoarticular, skin and soft tissue, pleuropulmonary, and device-related infections. This review comprehensively covers the epidemiology, pathophysiology, clinical manifestations, and management of each of these clinical entities. The past 2 decades have witnessed two clear shifts in the epidemiology of S. aureus infections: first, a growing number of health care-associated infections, particularly seen in infective endocarditis and prosthetic device infections, and second, an epidemic of community-associated skin and soft tissue infections driven by strains with certain virulence factors and resistance to β-lactam antibiotics. In reviewing the literature to support management strategies for these clinical manifestations, we also highlight the paucity of high-quality evidence for many key clinical questions.

Staphylococcus aureus Infections: Epidemiology, Pathophysiology, Clinical Manifestations, and Management

Chronic leg ulcers affect 1–2% of the general population and are related to increased morbidity and health costs. Staphylococcus aureus and Pseudomonas aeruginosa are the most common bacteria isolated from chronic wounds. They can express virulence factors and surface proteins affecting wound healing. The co-infection of S. aureus and P. aeruginosa is more virulent than single infection. In particular, S. aureus and P. aeruginosa have both intrinsic and acquired antibiotic resistance, making clinical management of infection a real challenge, particularly in patients with comorbidity. Therefore, a correct and prompt diagnosis of chronic wound infection requires a detailed knowledge of skin bacterial flora. This is a necessary prerequisite for tailored pharmacological treatment, improving symptoms, and reducing side effects and antibiotic resistance.

Chronic wound infections: the role of Pseudomonas aeruginosa and Staphylococcus aureus

Staphylococcus epidermidis is a permanent member of the normal human microbiota, commonly found on skin and mucous membranes. By adhering to tissue surface moieties of the host via specific adhesins, S. epidermidis is capable of establishing a lifelong commensal relationship with humans that begins early in life. In its role as a commensal organism, S. epidermidis is thought to provide benefits to human host, including out-competing more virulent pathogens. However, largely due to its capacity to form biofilm on implanted foreign bodies, S. epidermidis has emerged as an important opportunistic pathogen in patients receiving medical devices. S. epidermidis causes approximately 20% of all orthopedic device-related infections (ODRIs), increasing up to 50% in late-developing infections. Despite this prevalence, it remains underrepresented in the scientific literature, in particular lagging behind the study of the S. aureus. This review aims to provide an overview of the interactions of S. epidermidis with the human host, both as a commensal and as a pathogen. The mechanisms retained by S. epidermidis that enable colonization of human skin as well as invasive infection, will be described, with a particular focus upon biofilm formation. The host immune responses to these infections are also described, including how S. epidermidis seems to trigger low levels of pro-inflammatory cytokines and high levels of interleukin-10, which may contribute to the sub-acute and persistent nature often associated with these infections. The adaptive immune response to S. epidermidis remains poorly described, and represents an area which may provide significant new discoveries in the coming years.

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Pathogenic Mechanisms and Host Interactions in Staphylococcus epidermidis Device-Related Infection.

Propionibacterium acnes and Staphylococcus epidermidis live in close proximity on human skin, and both bacterial species can be isolated from normal and acne vulgaris-affected skin sites. The antagonistic interactions between the two species are poorly understood, as well as the potential significance of bacterial interferences for the skin microbiota. Here, we performed simultaneous antagonism assays to detect inhibitory activities between multiple isolates of the two species. Selected strains were sequenced to identify the genomic basis of their antimicrobial phenotypes. First, we screened 77 P. acnes strains isolated from healthy and acne-affected skin, and representing all known phylogenetic clades (I, II, and III), for their antimicrobial activities against 12 S. epidermidis isolates. One particular phylogroup (I-2) exhibited a higher antimicrobial activity than other P. acnes phylogroups. All genomes of type I-2 strains carry an island encoding the biosynthesis of a thiopeptide with possible antimicrobial activity against S. epidermidis. Second, 20 S. epidermidis isolates were examined for inhibitory activity against 25 P. acnes strains. The majority of S. epidermidis strains were able to inhibit P. acnes. Genomes of S. epidermidis strains with strong, medium and no inhibitory activities against P. acnes were sequenced. Genome comparison underlined the diversity of S. epidermidis and detected multiple clade- or strain-specific mobile genetic elements encoding a variety of functions important in antibiotic and stress resistance, biofilm formation and interbacterial competition, including bacteriocins such as epidermin. One isolate with an extraordinary antimicrobial activity against P. acnes harbors a functional ESAT-6 secretion system that might be involved in the antimicrobial activity against P. acnes via the secretion of polymorphic toxins. Taken together, our study suggests that interspecies interactions could potentially jeopardize balances in the skin microbiota. In particular, S. epidermidis strains possess an arsenal of different mechanisms to inhibit P. acnes. However, if such interactions are relevant in skin disorders such as acne vulgaris remains questionable, since no difference in the antimicrobial activity against, or the sensitivity towards S. epidermidis could be detected between health- and acne-associated strains of P. acnes.

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Antagonism between Staphylococcus epidermidis and Propionibacterium acnes and its genomic basis

The human nasal microbiota is highly variable and dynamic often enclosing major pathogens such as Staphylococcus aureus. The potential roles of bacteriocins or other mechanisms allowing certain bacterial clones to prevail in this nutrient-poor habitat have hardly been studied. Of 89 nasal Staphylococcus isolates, unexpectedly, the vast majority (84%) was found to produce antimicrobial substances in particular under habitat-specific stress conditions, such as iron limitation or exposure to hydrogen peroxide. Activity spectra were generally narrow but highly variable with activities against certain nasal members of the Actinobacteria, Proteobacteria, Firmicutes, or several groups of bacteria. Staphylococcus species and many other Firmicutes were insusceptible to most of the compounds. A representative bacteriocin was identified as a nukacin-related peptide whose inactivation reduced the capacity of the producer Staphylococcus epidermidis IVK45 to limit growth of other nasal bacteria. Of note, the bacteriocin genes were found on mobile genetic elements exhibiting signs of extensive horizontal gene transfer and rearrangements. Thus, continuously evolving bacteriocins appear to govern bacterial competition in the human nose and specific bacteriocins may become important agents for eradication of notorious opportunistic pathogens from human microbiota.

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High Frequency and Diversity of Antimicrobial Activities Produced by Nasal Staphylococcus Strains against Bacterial Competitors.

Staphylococci are abundant bacteria of the human skin microbiome. Several species, particularly Staphylococcus aureus and Staphylococcus epidermidis, are opportunistic pathogens and cause significant disease. The human skin serves many functions and here we review its role as an antimicrobial barrier and the staphylococcal mechanisms to colonize and counteract the various stresses present in this niche. Successful colonization is achieved using a diversity of adhesins, surface proteins and secreted enzymes to counteract the antimicrobial peptides, enzymes and lipid matrix components present in the acid mantle. Further mechanisms enable these bacteria to overcome osmotic and acid stresses and desiccation in order to survive the exacting demands of an ever-changing landscape.

Staphylococci: colonizers and pathogens of human skin

Staphylococcal colonization of human skin is ubiquitous, with particular species more frequent at different body sites. Whereas Staphylococcus epidermidis can be isolated from the skin of every individual tested, Staphylococcus aureus is isolated from <5% of healthy individuals. The factors that drive staphylococcal speciation and niche selection on skin are incompletely defined. Here we show that S. aureus is inhibited to a greater extent than S. epidermidis by the sebaceous lipid sapienic acid, supporting a role for this skin antimicrobial in selection of skin staphylococci. We used RNA-Seq and comparative transcriptomics to identify the sapienic acid survival responses of S. aureus and S. epidermidis. Consistent with the membrane depolarization mode of action of sapienic acid, both species shared a common transcriptional response to counteract disruption of metabolism and transport. The species differed in their regulation of SaeRS and VraRS regulons. While S. aureus upregulated urease operon transcription, S. epidermidis upregulated arginine deiminase, the oxygen-responsive NreABC nitrogen regulation system and the nitrate and nitrite reduction pathways. The role of S. aureus ACME and chromosomal arginine deiminase pathways in sapienic acid resistance was determined through mutational studies. We speculate that ammonia production could contribute to sapienic acid resistance in staphylococci.

Comparative Transcriptomics Reveals Discrete Survival Responses of S. aureus and S. epidermidis to Sapienic Acid.

Mannitol (Mtl) fermentation, with the subsequent production of acid, is a species signature of Staphylococcus aureus, and discriminates it from most other members of the genus. Inactivation of the gene mtlD, encoding Mtl-1-P dehydrogenase was found to markedly reduce survival in the presence of the antimicrobial fatty acid, linoleic acid. We demonstrate that the sugar alcohol has a potentiating action for this membrane-acting antimicrobial. Analysis of cellular metabolites revealed that, during exponential growth, the mtlD mutant accumulated high levels of Mtl and Mtl-P. The latter metabolite was not detected in its isogenic parent strain or a deletion mutant of the entire mtlABFD operon. In addition, the mtlD mutant strain exhibited a decreased MIC for H2O2, however virulence was unaffected in a model of septic arthritis.

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Mannitol utilisation is required for protection of Staphylococcus aureus from human skin antimicrobial fatty acids.

The bacterial genus Staphylococcus comprises diverse species with most being described as colonizers of human and animal skin. A relational analysis of features that discriminate its species and contribute to niche adaptation and survival remains to be fully described. In this study, an interspecies, whole-genome comparative analysis of 21 Staphylococcus species was performed based on their orthologues. Three well-defined multi-species groups were identified: group A (including aureus/epidermidis); group B (including saprophyticus/xylosus) and group C (including pseudintermedius/delphini). The machine learning algorithm Random Forest was applied to prioritize orthologs that drive formation of the Staphylococcus species groups A-C. Orthologues driving staphylococcal intrageneric diversity comprised regulatory, metabolic and antimicrobial resistance proteins. Notably, the BraSR (NsaRS) two-component system (TCS) and its associated BraDE transporters that regulate antimicrobial resistance showed limited distribution in the genus and their presence was most closely associated with a subset of Staphylococcus species dominated by those that colonize human skin. Divergence of BraSR and GraSR antimicrobial peptide survival TCS and their associated transporters was observed across the staphylococci, likely reflecting niche specific evolution of these TCS/transporters and their specificities for AMPs. Experimental evolution, with selection for resistance to the lantibiotic nisin, revealed multiple routes to resistance and differences in the selection outcomes of the BraSR-positive species S. hominis and S. aureus. Selection supported a role for GraSR in nisin survival responses of the BraSR-negative species S. saprophyticus. Our study reveals diversification of antimicrobial-sensing TCS across the staphylococci and hints at differential relationships between GraSR and BraSR in those species positive for both TCS.

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Comparative Genomics of Staphylococcus Reveals Determinants of Speciation and Diversification of Antimicrobial Defense.

We report here the genome sequence of a Commensalibacter sp. strain (AMU001) isolated from honey bees (Apis mellifera) from Seychelles. By combining long- and short-read sequencing technologies, we produced the first complete reference genome assembly for the Commensalibacter genus. We anticipate that this will aid future comparative and functional genomic studies.

https://journals.asm.org/doi/pdf/10.1128/MRA.01459-18

Josephine C. Moran

Papers

Staphylococci: colonizers and pathogens of human skin

Comparative Transcriptomics Reveals Discrete Survival Responses of S. aureus and S. epidermidis to Sapienic Acid.

Mannitol utilisation is required for protection of Staphylococcus aureus from human skin antimicrobial fatty acids.

Comparative Genomics of Staphylococcus Reveals Determinants of Speciation and Diversification of Antimicrobial Defense.

Complete Reference Genome Assembly for Commensalibacter sp. Strain AMU001, an Acetic Acid Bacterium Isolated from the Gut of Honey Bees.