Impact of sar and agr on methicillin resistance in Staphylococcus aureus

Durán, Segundo Píriz

doi:10.1016/0378-1097(96)00231-5

Cited by 11 publications

(11 citation statements)

References 9 publications

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“…It is also possible that fluoroquinolones have either direct or indirect effects on some global regulator(s) of S. aureus known to affect the expression of FnBP and other cell surface proteins (41) such as agr (33) or sar (44;; Chung and Wolz, 37th ICAAC). A recent report also indicates that agr-or sar-defective mutants express a somewhat lower level of methicillin resistance, which is associated with a reduction in levels of PBP1 and PBP3 but not PBP2Ј (8). While the present study, which was carried out with an agr knockout mutant, indicates that this global regulator is not required for the ciprofloxacin-induced response in fnbB transcription, further studies are in progress to evaluate the potential role of other global regulators, such as the sar locus or the more complex heat shock and SOS response systems.…”

Section: Discussionmentioning

confidence: 97%

Induction of Fibronectin-Binding Proteins and Increased Adhesion of Quinolone-ResistantStaphylococcus aureusby Subinhibitory Levels of Ciprofloxacin

Bisognano

Vaudaux

Rohner

et al. 2000

Antimicrob Agents Chemother

117

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We recently reported that strain EN1252a, a fluoroquinolone-resistant derivative of Staphylococcus aureus NCTC8325 with mutations in grlA and gyrA, expressed increased levels of fibronectin-binding proteins (FnBPs) and showed a significantly higher attachment to fibronectin-coated polymer surfaces after growth in the presence of subinhibitory concentrations of ciprofloxacin. The present study evaluated the occurrence and frequency of fluoroquinolone-induced FnBP-mediated adhesion in clinical isolates of fluoroquinolone-resistant methicillin-resistant S. aureus (MRSA) and methicillin-susceptible S. aureus (MSSA). Eight of ten MRSA isolates and four of six MSSA isolates with grlA and gyrA mutations exhibited significant increases in attachment to fibronectin-coated surfaces after growth in the presence of one-quarter the MIC of ciprofloxacin. Fluoroquinolone-induced FnBP-mediated adhesion of one clinical MRSA strain and the double mutant strain EN1252a also occurred on coverslips removed from the subcutaneous space of guinea pigs. For strain EN1252a, the regulation of fnb transcription by sub-MICs of ciprofloxacin was studied on reporter plasmids carrying fnb-luxAB fusions. One-quarter of the MIC of ciprofloxacin significantly increased fnbB, but not fnbA, promoter activity of the fluoroquinolone-resistant mutant but not its fluoroquinolone-susceptible parent ISP794. This response was abolished by pretreatment with rifampin, indicating an effect at the level of transcription. Activation of the fnbB promoter was not due to an indirect effect of ciprofloxacin on growth rate and still occurred in an agr mutant of strain EN1252a. These data suggest that sub-MIC levels of ciprofloxacin activate the fnbB promoter of some laboratory and clinical isolates, thus contributing to increased production of FnBP(s) and leading to higher levels of bacterial attachment to fibronectin-coated or subcutaneously implanted coverslips.

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Section: Discussionmentioning

confidence: 97%

Induction of Fibronectin-Binding Proteins and Increased Adhesion of Quinolone-ResistantStaphylococcus aureusby Subinhibitory Levels of Ciprofloxacin

Bisognano

Vaudaux

Rohner

et al. 2000

Antimicrob Agents Chemother

117

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“…2001). Genetically engineered agr mutants demonstrate a reproducible decrease in beta-lactam resistance compared to isogenic parent strains (10). Transcription profiling technology has identified femB, a gene required for the full expression of mec-mediated methicillin resistance, to be under the regulation of agr (9).…”

Section: Discussionmentioning

confidence: 99%

“…Overnight cultures were diluted 1:800 in BHI broth to obtain a starting inoculum of ca. 10 6 CFU/ml, to which was added 16 g of vancomycin/ml. Samples obtained at 0, 4, 24, and 48 h and then daily thereafter for 5 days were serially diluted from 10 to 10 7 .…”

Section: Methodsmentioning

confidence: 99%

Accessory Gene Regulator ( agr ) Locus in Geographically Diverse Staphylococcus aureus Isolates with Reduced Susceptibility to Vancomycin

Sakoulas

Eliopoulos

Moellering

et al. 2002

Antimicrob Agents Chemother

337

308

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The majority of infections with glycopeptide intermediate-level resistant Staphylococcus aureus (GISA) originate in biomedical devices, suggesting a possible increased ability of these strains to produce biofilm. Loss of function of the accessory gene regulator (agr) of S. aureus has been suggested to confer an enhanced ability to bind to polystyrene. We studied agr in GISA, hetero-GISA, and related glycopeptide-susceptible S. aureus isolates. All GISA strains from diverse geographic origins belong to agr group II. All GISA strains were defective in agr function, as demonstrated by their inability to produce delta-hemolysin. Hetero-GISA isolate A5940 demonstrated a nonsense mutation in agrA that was not present in a pulsed-field gel electrophoresisindistinguishable vancomycin-susceptible isolate from the same patient. Various other agr point mutations were noted in several clinical GISA and hetero-GISA isolates. A laboratory-generated agr-null strain demonstrated a small but reproducible increase in vancomycin heteroresistance after growth in vitro in subinhibitory concentrations of vancomycin. This was not seen in the isogenic agr group II parent strain in which agr was intact. The in vitro bactericidal activity of vancomycin was attenuated in the agr-null strain compared to the parent strain. These findings imply that compromised agr function is advantageous to clinical isolates of S. aureus toward the development of vancomycin heteroresistance, perhaps through the development of vancomycin tolerance.Since 1997, several case reports have appeared describing Staphylococcus aureus clinical isolates with reduced susceptibility to glycopeptide antibiotics (5, 11, 13-15, 32, 35, 36). The mechanisms responsible for this low-level resistance are poorly understood but do not involve the vanA, vanB, vanC, vanD, vanE, or vanG genes that confer vancomycin resistance in enterococci (12-15). The preponderance of data suggests that the mechanism for intermediate-level vancomycin resistance in S. aureus may relate to sequestration of the antimicrobial agent by nonamidated muropeptides within a thickened cell wall (8,12,13).Our review of clinical case histories of several patients with glycopeptide intermediate-level resistant S. aureus (GISA) strains revealed that, in addition to prolonged exposure to vancomycin, most of these patients had infections originating in or involving biomedical devices such as artificial heart valves, central venous catheters, biliary stents, and dialysis catheters (5, 11, 13-15, 32, 35, 36).The accessory gene regulator (agr) locus of S. aureus is a quorum-sensing gene cluster of five genes (hld, agrB, agrD, agrC, and agrA) that upregulates production of secreted virulence factors, including the alpha-, beta-, and delta-hemolysins, and downregulates production of cell-associated virulence factors (16,23,25,26,28,31). Polymorphisms in agrD and agrC define four S. aureus agr groups (25). Published reports have noted that agr group I strains comprised a significant majority of clinical isolates (...

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“…Examples of fem/aux factors linked to the cell envelope include cell wall biosynthesis enzymes like GlmM [11], MurE [12], MurF [13], FemABX [14], PBP2 [15], PBP4 [16]; and wall teichoic acid biosynthesis enzymes including TagO/TarO [17], the dlt operon [18] and the wall teichoic acid ligase MsrR [19], [20]. Fem/aux factors indirectly connected or with no obvious connection to the cell envelope include regulators like SigB [21], SpoVG [22], agr [23], SarA [23], XdrA [24], CcpA [25], SecDF [26] or two component systems like VraSR [27], [28].…”

Section: Introductionmentioning

confidence: 99%

Mutation in the C-Di-AMP Cyclase dacA Affects Fitness and Resistance of Methicillin Resistant Staphylococcus aureus

et al. 2013

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Faster growing and more virulent strains of methicillin resistant Staphylococcus aureus (MRSA) are increasingly displacing highly resistant MRSA. Elevated fitness in these MRSA is often accompanied by decreased and heterogeneous levels of methicillin resistance; however, the mechanisms for this phenomenon are not yet fully understood. Whole genome sequencing was used to investigate the genetic basis of this apparent correlation, in an isogenic MRSA strain pair that differed in methicillin resistance levels and fitness, with respect to growth rate. Sequencing revealed only one single nucleotide polymorphism (SNP) in the diadenylate cyclase gene dacA in the faster growing but less resistant strain. Diadenylate cyclases were recently discovered to synthesize the new second messenger cyclic diadenosine monophosphate (c-di-AMP). Introduction of this mutation into the highly resistant but slower growing strain reduced resistance and increased its growth rate, suggesting a direct connection between the dacA mutation and the phenotypic differences of these strains. Quantification of cellular c-di-AMP revealed that the dacA mutation decreased c-di-AMP levels resulting in reduced autolysis, increased salt tolerance and a reduction in the basal expression of the cell wall stress stimulon. These results indicate that c-di-AMP affects cell envelope-related signalling in S. aureus. The influence of c-di-AMP on growth rate and methicillin resistance in MRSA indicate that altering c-di-AMP levels could be a mechanism by which MRSA strains can increase their fitness levels by reducing their methicillin resistance levels.

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Impact of sar and agr on methicillin resistance in Staphylococcus aureus

Cited by 11 publications

References 9 publications

Induction of Fibronectin-Binding Proteins and Increased Adhesion of Quinolone-ResistantStaphylococcus aureusby Subinhibitory Levels of Ciprofloxacin

Induction of Fibronectin-Binding Proteins and Increased Adhesion of Quinolone-ResistantStaphylococcus aureusby Subinhibitory Levels of Ciprofloxacin

Accessory Gene Regulator ( agr ) Locus in Geographically Diverse Staphylococcus aureus Isolates with Reduced Susceptibility to Vancomycin

Mutation in the C-Di-AMP Cyclase dacA Affects Fitness and Resistance of Methicillin Resistant Staphylococcus aureus

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