scholarly journals Evolution of Staphylococcus aureus under Vancomycin Selective Pressure: the Role of the Small-Colony Variant Phenotype

2014 ◽  
Vol 59 (2) ◽  
pp. 1347-1351 ◽  
Author(s):  
Justin R. Lenhard ◽  
Christof von Eiff ◽  
Irene S. Hong ◽  
Patricia N. Holden ◽  
Michael D. Bear ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Antibiotic Therapy ◽  
Selective Pressure ◽  
Type Model ◽  
Methicillin Resistant ◽  
Small Colony Variants ◽  
Content Type ◽  
Small Colony Variant ◽  
Small Colony

ABSTRACTStaphylococcus aureussmall-colony variants (SCVs) often persist despite antibiotic therapy. Against a 108-CFU/ml methicillin-resistantS. aureus(MRSA) (strain COL) population of which 0%, 1%, 10%, 50%, or 100% was an isogenichemBknockout (Ia48) subpopulation displaying the SCV phenotype, vancomycin achieved maximal reductions of 4.99, 5.39, 4.50, 3.28, and 1.66 log10CFU/ml over 48 h. Vancomycin at ≥16 mg/liter shifted a population from 50% SCV cells at 0 h to 100% SCV cells at 48 h, which was well characterized by a Hill-type model (R2> 0.90).

scholarly journals The MpsB protein contributes to both the toxicity and immune evasion capacity of Staphylococcus aureus

Microbiology ◽  
2021 ◽  
Vol 167 (10) ◽  
Author(s):  
Edward J. A. Douglas ◽  
Seána Duggan ◽  
Tarcisio Brignoli ◽  
Ruth C. Massey
Keyword(s):  
Staphylococcus Aureus ◽  
Immune Evasion ◽  
Type Species ◽  
Severe Disease ◽  
Toxin Production ◽  
Content Type ◽  
Small Colony Variant ◽  
Link Type ◽  
Small Colony

Understanding the role specific bacterial factors play in the development of severe disease in humans is critical if new approaches to tackle such infections are to be developed. In this study we focus on genes we have found to be associated with patient outcome following bacteraemia caused by the major human pathogen Staphylococcus aureus . By examining the contribution these genes make to the ability of the bacteria to survive exposure to the antibacterial factors found in serum, we identify three novel serum resistance-associated genes, mdeA, mpsB and yycH. Detailed analysis of an MpsB mutant supports its previous association with the slow growing small colony variant (SCV) phenotype of S. aureus , and we demonstrate that the effect this mutation has on membrane potential prevents the activation of the Agr quorum sensing system, and as a consequence the mutant bacteria do not produce cytolytic toxins. Given the importance of both toxin production and immune evasion for the ability of S. aureus to cause disease, we believe that these findings explain the role of the mpsB gene as a mortality-associated locus during human disease.

scholarly journals Enhanced production of exopolysaccharide matrix and biofilm by a menadione-auxotrophic Staphylococcus aureus small-colony variant

2010 ◽  
Vol 59 (5) ◽  
pp. 521-527 ◽  
Author(s):  
Rachna Singh ◽  
Pallab Ray ◽  
Anindita Das ◽  
Meera Sharma
Keyword(s):  
Staphylococcus Aureus ◽  
Tricarboxylic Acid Cycle ◽  
Surface Hydrophobicity ◽  
Tricarboxylic Acid ◽  
Polysaccharide Intercellular Adhesin ◽  
Wild Type ◽  
Small Colony Variant ◽  
Enhanced Production ◽  
Small Colony

The role of Staphylococcus aureus small-colony variants (SCVs) in the pathogenesis of biofilm-associated infections remains unclear. This study investigated the mechanism behind increased biofilm-forming potential of a menadione-auxotrophic Staphylococcus aureus SCV compared with the wild-type parental strain, as recently reported by our laboratory. SCVs displayed an autoaggregative phenotype, with a greater amount of polysaccharide intercellular adhesin (PIA), significantly reduced tricarboxylic acid cycle activity and a decreased susceptibility to aminoglycosides and cell-wall inhibitors compared with wild-type. The biofilms formed by the SCV were highly structured, consisting of large microcolonies separated by channels, and contained more biomass as well as significantly more PIA than wild-type biofilms. The surface hydrophobicity of the two phenotypes was similar. Thus, the autoaggregation and increased biofilm-forming capacity of menadione-auxotrophic Staphylococcus aureus SCVs in this study was related to the enhanced production of PIA in these variants.

scholarly journals Inactivation of thyA in Staphylococcus aureus Attenuates Virulence and Has a Strong Impact on Metabolism and Virulence Gene Expression

mBio ◽  
2014 ◽  
Vol 5 (4) ◽  
Author(s):  
Andre Kriegeskorte ◽  
Desiree Block ◽  
Mike Drescher ◽  
Nadine Windmüller ◽  
Alexander Mellmann ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Thymidylate Synthase ◽  
Molecular Basis ◽  
De Novo ◽  
Strong Impact ◽  
Small Colony Variants ◽  
Content Type ◽  
Long Term Treatment ◽  
Small Colony ◽  
The Impact

ABSTRACTStaphylococcus aureusthymidine-dependent small-colony variants (TD-SCVs) are frequently isolated from patients with chronicS. aureusinfections after long-term treatment with trimethoprim-sulfamethoxazole (TMP-SMX). While it has been shown that TD-SCVs were associated with mutations in thymidylate synthase (TS;thyA), the impact of such mutations on protein function is lacking. In this study, we showed that mutations inthyAwere leading to inactivity of TS proteins, and TS inactivity led to tremendous impact onS. aureusphysiology and virulence. Whole DNA microarray analysis of the constructed ΔthyAmutant identified severe alterations compared to the wild type. Important virulence regulators (agr,arlRS,sarA) and major virulence determinants (hla,hlb,sspAB, andgeh) were downregulated, while genes important for colonization (fnbA,fnbB,spa,clfB,sdrC, andsdrD) were upregulated. The expression of genes involved in pyrimidine and purine metabolism and nucleotide interconversion changed significantly. NupC was identified as a major nucleoside transporter, which supported growth of the mutant during TMP-SMX exposure by uptake of extracellular thymidine. The ΔthyAmutant was strongly attenuated in virulence models, including aCaenorhabditis eleganskilling model and an acute pneumonia mouse model. This study identified inactivation of TS as the molecular basis of clinical TD-SCV and showed thatthyAactivity has a major role forS. aureusvirulence and physiology.IMPORTANCEThymidine-dependent small-colony variants (TD-SCVs) ofStaphylococcus aureuscarry mutations in the thymidylate synthase (TS) gene (thyA) responsible forde novosynthesis of thymidylate, which is essential for DNA synthesis. TD-SCVs have been isolated from patients treated for long periods with trimethoprim-sulfamethoxazole (TMP-SMX) and are associated with chronic and recurrent infections. In the era of community-associated methicillin-resistantS. aureus, the therapeutic use of TMP-SMX is increasing. Today, the emergence of TD-SCVs is still underestimated due to misidentification in the diagnostic laboratory. This study showed for the first time that mutational inactivation of TS is the molecular basis for the TD-SCV phenotype and that TS inactivation has a strong impact onS. aureusvirulence and physiology. Our study helps to understand the clinical nature of TD-SCVs, which emerge frequently once patients are treated with TMP-SMX.

scholarly journals Attenuated Virulence and Biofilm Formation in Staphylococcus aureus following Sublethal Exposure to Triclosan

2012 ◽  
Vol 56 (6) ◽  
pp. 3092-3100 ◽  
Author(s):  
Joe Latimer ◽  
Sarah Forbes ◽  
Andrew J. McBain
Keyword(s):  
Staphylococcus Aureus ◽  
Growth Rate ◽  
Growth Rates ◽  
Biofilm Formation ◽  
Galleria Mellonella ◽  
Concentration Gradients ◽  
Content Type ◽  
Small Colony Variant ◽  
Small Colony ◽  
Repeated Passage

ABSTRACTSubeffective exposure ofStaphylococcus aureusto the biocide triclosan can reportedly induce a small-colony variant (SCV) phenotype.S. aureusSCVs are characterized by low growth rates, reduced pigmentation, and lowered antimicrobial susceptibility. While they may exhibit enhanced intracellular survival, there are conflicting reports regarding their pathogenicity. The current study reports the characteristics of an SCV-like strain ofS. aureuscreated by repeated passage on sublethal triclosan concentrations.S. aureusATCC 6538 (the passage 0 [P0] strain) was serially exposed 10 times to concentration gradients of triclosan to generate strain P10. This strain was then further passaged 10 times on triclosan-free medium (designated strain ×10). The MICs and minimum bactericidal concentrations of triclosan for P0, P10, and ×10 were determined, and growth rates in biofilm and planktonic cultures were measured. Hemolysin, DNase, and coagulase activities were measured, and virulence was determined using aGalleria mellonellapathogenicity model. Strain P10 exhibited decreased susceptibility to triclosan and characteristics of an SCV phenotype, including a considerably reduced growth rate and the formation of pinpoint colonies. However, this strain also had delayed coagulase production, had impaired hemolysis (P< 0.01), was defective in biofilm formation and DNase activity, and displayed significantly attenuated virulence. Colony size, hemolysis, coagulase activity, and virulence were only partially restored in strain ×10, whereas the planktonic growth rate was fully restored. However, ×10 was at least as defective in biofilm formation and DNase production as P10. These data suggest that although repeated exposure to triclosan may result in an SCV-like phenotype, this is not necessarily associated with increased virulence and adapted bacteria may exhibit other functional deficiencies.

scholarly journals Identification of Point Mutations in Clinical Staphylococcus aureus Strains That Produce Small-Colony Variants Auxotrophic for Menadione

2014 ◽  
Vol 82 (4) ◽  
pp. 1600-1605 ◽  
Author(s):  
Melissa A. Dean ◽  
Randall J. Olsen ◽  
S. Wesley Long ◽  
Adriana E. Rosato ◽  
James M. Musser
Keyword(s):  
Staphylococcus Aureus ◽  
Pathway Analysis ◽  
Molecular Mechanisms ◽  
Point Mutations ◽  
Biosynthesis Pathway ◽  
Wild Type ◽  
Small Colony Variants ◽  
Content Type ◽  
Genes Encoding ◽  
Small Colony

ABSTRACTStaphylococcus aureussmall-colony variants (SCVs) are implicated in chronic and relapsing infections that are difficult to diagnose and treat. Despite many years of study, the underlying molecular mechanisms and virulence effect of the small-colony phenotype remain incompletely understood. We sequenced the genomes of fiveS. aureusSCV strains recovered from human patients and discovered previously unidentified nonsynonymous point mutations in three genes encoding proteins in the menadione biosynthesis pathway. Analysis of genetic revertants and complementation with wild-type alleles confirmed that these mutations caused the SCV phenotype and decreased virulence for mice.

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