Therapeutic Targeting of the Staphylococcus aureus Accessory Gene Regulator (agr) System

Tan, Li; Li, Si Rui; Jiang, Bei; Hu, Xiao M; Li, Shu

doi:10.3389/fmicb.2018.00055

Cited by 165 publications

(119 citation statements)

References 95 publications

(153 reference statements)

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“…Nevertheless, in our study all CC97 isolates belonged to agr type III, which may be characteristic of ST2855 since in the only study reporting ST2855 in rabbits, all ST2855 isolates from farm rabbit infections were also typed as agr III [31]. Studies have tried to find a relationship between the type of agr and the type of infections and toxins produced by S. aureus and, although agr III MRSA isolates are often tst-positive, in our study the tst gene was not identified [47,48].…”

Section: Characterization Of Cc97 Mrsa Isolatesmentioning

confidence: 56%

Livestock-Associated Methicillin-Resistant Staphylococcus aureus (MRSA) in Purulent Subcutaneous Lesions of Farm Rabbits

Silva

Sousa

Gómez

et al. 2020

Foods

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Methicillin-resistant Staphylococcus aureus (MRSA) are one of the main pathogens associated with purulent infections. MRSA clonal complex 97 (CC97) has been identified in a wide diversity of livestock animals. Therefore, we aimed to investigate the antibiotic resistance profiles of MRSA strains isolated from purulent lesions of food-producing rabbits. Samples from purulent lesions of 66 rabbits were collected in a slaughterhouse in Portugal. Samples were seeded onto ORSAB plates with 2 mg/L of oxacillin for MRSA isolation. Susceptibility to antibiotics was tested by the disk diffusion method against 14 antimicrobial agents. The presence of resistance genes, virulence factors and the immune evasion cluster (IEC) system was studied by polymerase chain reaction. All isolates were characterized by multilocus sequence typing (MLST), agr and spa typing. From the 66 samples analyzed, 16 (24.2%) MRSA were detected. All strains were classified as multidrug-resistant as they were resistant to at least three classes of antibiotics. All isolates showed resistance to penicillin, erythromycin and clindamycin. Seven isolates were resistant to gentamicin and harbored the aac(6 )-Ie-aph (2 )-Ia gene. Resistance to tetracycline was detected in 10 isolates harboring the tet(K) gene. The IEC genes were detected in three isolates. MRSA strains belonged to CC97, CC1, CC5, CC15 or CC22. The isolates were assigned to six different spa types. In this study we found a moderate prevalence of multidrug-resistant MRSA strains in food-producing rabbits. This may represent concern for food Foods 2020, 9, 439; doi:10.3390/foods9040439 www.mdpi.com/journal/foods Foods 2020, 9, 439 2 of 10 safety and public health, since cross-contamination may occur, leading to the spread of MRSA and, eventually, the possibility of ingestion of contaminated meat.

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Section: Characterization Of Cc97 Mrsa Isolatesmentioning

confidence: 56%

Livestock-Associated Methicillin-Resistant Staphylococcus aureus (MRSA) in Purulent Subcutaneous Lesions of Farm Rabbits

Silva

Sousa

Gómez

et al. 2020

Foods

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“…JE2 was known as agr type I, which was confirmed by our sequence analysis. None of our isolates were agr type IV; this reflects the phylogeny of the strains and what is known about agr type IV due to its main association with isolates from skin infections [40].…”

Section: Resultsmentioning

confidence: 89%

Genotypic and phenotypic diversity ofStaphylococcus aureusfrom cystic fibrosis lung infections and their interactions withPseudomonas aeruginosa

Petit

Raghuram

et al. 2019

Preprint

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20Pseudomonas aeruginosa and Staphylococcus aureus are the most common bacteria 21 that infect the respiratory tract of individuals with the genetic disease cystic fibrosis (CF); in fact, 22S. aureus has recently overtaken P. aeruginosa to become the most common. Substantial 23 research has been performed on the epidemiology of S. aureus in CF; however, there appears 24 to be a gap in knowledge in regard to the pathogenesis of S. aureus in the context of CF lung 25 infections. Most studies have focused on a few S. aureus isolates, often exclusively laboratory 26 adapted strains, and how they are killed by P. aeruginosa. Because of this, little is known about 27 the diversity of S. aureus CF lung isolates in both virulence and interaction with P. aeruginosa. 28To begin to address this gap in knowledge, we recently sequenced 65 clinical S. aureus isolates 29 from the Emory CF Biospecimen Registry and Boston Children's Hospital, including the 30 reference isolate JE2, a USA300 strain. Here, we analyzed antibiotic resistance genotypes, 31 sequence type, clonal complex, spa type, and agr type of these isolates. We hypothesized that 32 major virulence phenotypes of S. aureus that may be associated with CF lung infections, 33 namely toxin production and mucoid phenotype, would be retained in these isolates. To test our 34 hypothesis, we plated on specific agars and found that most isolates can hemolyze both rabbit 35 and sheep blood (67.7%) and produce polysaccharide (69.2%), consistent with virulence 36 retention in CF lung isolates. We also identified three distinct phenotypic groups of S. aureus 37 based on their survival in the presence of nonmucoid P. aeruginosa laboratory strain PAO1 and 38 its mucoid derivative. Altogether, our work provides greater insight into the diversity of S. aureus 39 CF isolates, specifically the distribution of important virulence factors and their interaction with 40 P. aeruginosa, all of which have implications in patient health. 41 42 Author Summary 43Staphylococcus aureus is now the most frequently detected pathogen in the lungs of 44 individuals who have cystic fibrosis (CF), followed closely by Pseudomonas aeruginosa. When 45 these two pathogens are found to coinfect the CF lung, patients have a significantly worse 46 prognosis. While P. aeruginosa has been rigorously studied in the context of bacterial 47 pathogenesis in CF, less is known about S. aureus. Here we present an in-depth study of 64 S. 48 aureus CF clinical isolates where we investigated genetic diversity utilizing whole genome 49 sequencing, virulence phenotypes, and interactions with P. aeruginosa. We have found that S. 50 aureus isolated from the CF lung are phylogenetically diverse, most retain known virulence 51 factors, and they vary in interactions with P. aeruginosa from highly sensitive to completely 52 tolerant. Deepening our understanding of how S. aureus responds to its environment and other 53 microbes in the CF lung will enable future development of effective treatments and preventative 54 measures agains...

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“…Altogether, this work has expanded our understanding of the regulatory inputs that dictate cyclic peptide quorum sensing in S. aureus. Our studies represent an expansion of the Agr regulatory circuit that may have broad impacts on therapeutic design for noncomplicated infection (12,14,(88)(89)(90). Further, the work highlights the complexities of peptide-based signaling and the adaptive traits that promote virulence in S. aureus.…”

Section: Discussionmentioning

confidence: 91%

Control of Staphylococcus aureus Quorum Sensing by a Membrane-Embedded Peptidase

et al. 2019

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Gram-positive bacteria process and release small peptides, or pheromones, that act as signals for the induction of adaptive traits, including those involved in pathogenesis. One class of small signaling pheromones is the cyclic autoinducing peptides (AIPs), which regulate expression of genes that orchestrate virulence and persistence in a range of microbes, including staphylococci, listeriae, clostridia, and enterococci. In a genetic screen for Staphylococcus aureus secreted virulence factors, we identified an S. aureus mutant containing an insertion in the gene SAUSA300_1984 (mroQ), which encodes a putative membrane-embedded metalloprotease. A ΔmroQ mutant exhibited impaired induction of Toll-like receptor 2-dependent inflammatory responses from macrophages but elicited greater production of the inflammatory cytokine interleukin-1␤ and was attenuated in a murine skin and soft tissue infection model. The ΔmroQ mutant phenocopies an S. aureus mutant containing a deletion of the accessory gene regulatory system (Agr), wherein both strains have significantly reduced production of secreted toxins and virulence factors but increased surface protein A abundance. The Agr system controls virulence factor gene expression in S. aureus by sensing the accumulation of AIP via the histidine kinase AgrC and the response regulator AgrA. We provide evidence to suggest that MroQ acts within the Agr pathway to facilitate the optimal processing or export of AIP for signal amplification through AgrC/A and induction of virulence factor gene expression. Mutation of MroQ active-site residues significantly reduces AIP signaling and attenuates virulence. Altogether, this work identifies a new component of the Agr quorum-sensing circuit that is critical for the production of S. aureus virulence factors.

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Therapeutic Targeting of the Staphylococcus aureus Accessory Gene Regulator (agr) System

Cited by 165 publications

References 95 publications

Livestock-Associated Methicillin-Resistant Staphylococcus aureus (MRSA) in Purulent Subcutaneous Lesions of Farm Rabbits

Livestock-Associated Methicillin-Resistant Staphylococcus aureus (MRSA) in Purulent Subcutaneous Lesions of Farm Rabbits

Genotypic and phenotypic diversity ofStaphylococcus aureusfrom cystic fibrosis lung infections and their interactions withPseudomonas aeruginosa

Control of Staphylococcus aureus Quorum Sensing by a Membrane-Embedded Peptidase

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