Dataset Information

Coagulase-Negative Staphylococcal Strain Prevents Staphylococcus aureus Colonization and Skin Infection by Blocking Quorum Sensing.

ABSTRACT: Coagulase-negative staphylococci (CoNS) and Staphylococcus aureus are part of the natural flora of humans and other mammals. We found that spent media from the CoNS species Staphylococcus caprae can inhibit agr-mediated quorum sensing by all classes of S. aureus. A biochemical assessment of the inhibitory activity suggested that the S. caprae autoinducing peptide (AIP) was responsible, and mass spectrometric analysis identified the S. caprae AIP as an eight-residue peptide (YSTCSYYF). Using a murine model of intradermal MRSA infection, the therapeutic efficacy of synthetic S. caprae AIP was evident by a dramatic reduction in both dermonecrotic injury and cutaneous bacterial burden relative to controls. Competition experiments between S. caprae and MRSA demonstrated a significant reduction in MRSA burden using murine models of both skin colonization and intradermal infection. Our findings indicate that important interactions occur between commensals that can impact disease outcomes and potentially shape the composition of the natural flora.

SUBMITTER: Paharik AE

PROVIDER: S-EPMC5897044 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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Coagulase-Negative Staphylococcal Strain Prevents Staphylococcus aureus Colonization and Skin Infection by Blocking Quorum Sensing.

Paharik Alexandra E AE Parlet Corey P CP Chung Nadjali N Todd Daniel A DA Rodriguez Emilio I EI Van Dyke Michael J MJ Cech Nadja B NB Horswill Alexander R AR

Cell host & microbe 20171130 6

Coagulase-negative staphylococci (CoNS) and Staphylococcus aureus are part of the natural flora of humans and other mammals. We found that spent media from the CoNS species Staphylococcus caprae can inhibit agr-mediated quorum sensing by all classes of S. aureus. A biochemical assessment of the inhibitory activity suggested that the S. caprae autoinducing peptide (AIP) was responsible, and mass spectrometric analysis identified the S. caprae AIP as an eight-residue peptide (YSTCSYYF). Using a mu ...[more]

PMID: 29199097

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Project description:Staphylococci are associated with both humans and animals. While most are non-pathogenic colonizers, Staphylococcus aureus is an opportunistic pathogen capable of causing severe infections. S. aureus virulence is controlled by the agr quorum sensing system responding to secreted auto-inducing peptides (AIPs) sensed by AgrC, a two component histidine kinase. agr loci are found also in other staphylococcal species and for Staphylococcus epidermidis, the encoded AIP represses expression of agr regulated virulence genes in S. aureus. In this study we aimed to better understand the interaction between staphylococci and S. aureus, and show that this interaction may eventually lead to the identification of new anti-virulence candidates to target S. aureus infections. Here we show that culture supernatants of 37 out of 52 staphylococcal isolates representing 17 different species inhibit S. aureus agr. The dog pathogen, Staphylococcus schleiferi, expressed the most potent inhibitory activity and was active against all four agr classes found in S. aureus. By employing a S. aureus strain encoding a constitutively active AIP receptor we show that the activity is mediated via agr. Subsequent cloning and heterologous expression of the S. schleiferi AIP in S. aureus demonstrated that this molecule was likely responsible for the inhibitory activity, and further proof was provided when pure synthetic S. schleiferi AIP was able to completely abolish agr induction of an S. aureus reporter strain. To assess impact on S. aureus virulence, we co-inoculated S. aureus and S. schleiferi in vivo in the Galleria mellonella wax moth larva, and found that expression of key S. aureus virulence factors was abrogated. Our data show that the S. aureus agr locus is highly responsive to other staphylococcal species suggesting that agr is an inter-species communication system. Based on these results we speculate that interactions between S. aureus and other colonizing staphylococci will significantly influence the ability of S. aureus to cause infection, and we propose that other staphylococci are potential sources of compounds that can be applied as anti-virulence therapy for combating S. aureus infections.

Project description:UnlabelledStaphylococcus aureus is a human commensal that at times turns into a serious bacterial pathogen causing life-threatening infections. For the delicate control of virulence, S. aureus employs the agr quorum-sensing system that, via the intracellular effector molecule RNAIII, regulates virulence gene expression. We demonstrate that the presence of the agr locus imposes a fitness cost on S. aureus that is mediated by the expression of RNAIII. Further, we show that exposure to sublethal levels of the antibiotics ciprofloxacin, mupirocin, and rifampin, each targeting separate cellular functions, markedly increases the agr-mediated fitness cost by inducing the expression of RNAIII. Thus, the extensive use of antibiotics in hospitals may explain why agr-negative variants are frequently isolated from hospital-acquired S. aureus infections but rarely found among community-acquired S. aureus strains. Importantly, agr deficiency correlates with increased duration of and mortality due to bacteremia during antibiotic treatment and with a higher frequency of glycopeptide resistance than in agr-carrying strains. Our results provide an explanation for the frequent isolation of agr-defective strains from hospital-acquired S. aureus infections and suggest that the adaptability of S. aureus to antibiotics involves the agr locus.ImportanceStaphylococcus aureus is the most frequently isolated pathogen in intensive care units and a common cause of nosocomial infections, resulting in a high degree of morbidity and mortality. Surprisingly, a large fraction (15 to 60%) of hospital-isolated S. aureus strains are agr defective and lack the main quorum-sensing-controlled virulence regulatory system. This is a problem, as agr-defective strains are associated with a mortality level in bacteremic infections and a probability of glycopeptide resistance greater than those of other strains. We show here that agr-negative strains have a fitness advantage over agr-positive strains in the presence of sublethal concentrations of some antibiotics and that the fitness defect of agr-positive cells is caused by antibiotic-mediated expression of the agr effector molecule RNAIII. These results offer an explanation of the frequent isolation of agr-defective S. aureus strains in hospitals and will influence how we treat S. aureus infections.

Dataset Information

Coagulase-Negative Staphylococcal Strain Prevents Staphylococcus aureus Colonization and Skin Infection by Blocking Quorum Sensing.

Publications

Coagulase-Negative Staphylococcal Strain Prevents Staphylococcus aureus Colonization and Skin Infection by Blocking Quorum Sensing.

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