scholarly journals Causal Role of Single Nucleotide Polymorphisms within themprFGene of Staphylococcus aureus in Daptomycin Resistance

2013 ◽  
Vol 57 (11) ◽  
pp. 5658-5664 ◽  
Author(s):  
Soo-Jin Yang ◽  
Nagendra N. Mishra ◽  
Aileen Rubio ◽  
Arnold S. Bayer
Keyword(s):  
Staphylococcus Aureus ◽  
Single Nucleotide Polymorphisms ◽  
Point Mutations ◽  
Nucleotide Polymorphisms ◽  
Wild Type ◽  
Single Nucleotide ◽  
Content Type ◽  
Reading Frame ◽  
A Charge

ABSTRACTSingle nucleotide polymorphisms (SNPs) within themprFopen reading frame (ORF) have been commonly observed in daptomycin-resistant (DAPr)Staphylococcus aureusstrains. Such SNPs are usually associated with a gain-in-function phenotype, in terms of either increased synthesis or enhanced translocation (flipping) of lysyl-phosphatidylglycerol (L-PG). However, it is unclear if suchmprFSNPs are causal in DAPrstrains or are merely a biomarker for this phenotype. In this study, we used an isogenic set ofS. aureusstrains: (i) Newman, (ii) its isogenic ΔmprFmutant, and (iii) several intransplasmid complementation constructs, expressing either a wild-type or point-mutated form of themprFORF cloned from two isogenic DAP-susceptible (DAPs)-DAPrstrain pairs (616-701 and MRSA11/11-REF2145). Complementation of the ΔmprFstrain with singly point-mutatedmprFgenes (mprFS295LormprFT345A) revealed that (i) individual and distinct point mutations within themprFORF can recapitulate phenotypes observed in donor strains (i.e., changes in DAP MICs, positive surface charge, and cell membrane phospholipid profiles) and (ii) these gain-in-function SNPs (i.e., enhanced L-PG synthesis) likely promote reduced DAP binding toS. aureusby a charge repulsion mechanism. Thus, for these two DAPrstrains, the definedmprFSNPs appear to be causally related to this phenotype.

scholarly journals Evolution and Single-Nucleotide Polymorphisms in Methicillin-Resistant Staphylococcus aureus Strains with Reduced Susceptibility to Vancomycin and Daptomycin, Based on Determination of the Complete Genome

2015 ◽  
Vol 59 (6) ◽  
pp. 3585-3587 ◽  
Author(s):  
Tetsuo Yamaguchi ◽  
Shingo Suzuki ◽  
Sakiko Okamura ◽  
Yuri Miura ◽  
Ayaka Tsukimori ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Single Nucleotide Polymorphisms ◽  
Complete Genome ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Methicillin Resistant ◽  
Content Type ◽  
Rifampin Resistance ◽  
Generation Sequencing

ABSTRACTWe obtained a series of methicillin-resistantStaphylococcus aureusisolates, including both daptomycin-susceptible strain TD1 and daptomycin-resistant strain TD4, from a patient. We determined the complete genome sequences of TD1 and TD4 using next-generation sequencing, and only four single-nucleotide polymorphisms (SNPs) were identified, one each incapB(E58K),rpoB(H481Y),lytN(I16V), andmprF(V351E). We determined that these four SNPs were sufficient to cause the strains to develop daptomycin, vancomycin, and rifampin resistance.

scholarly journals Frequency and Distribution of Single-Nucleotide Polymorphisms withinmprFin Methicillin-Resistant Staphylococcus aureus Clinical Isolates and Their Role in Cross-Resistance to Daptomycin and Host Defense Antimicrobial Peptides

2015 ◽  
Vol 59 (8) ◽  
pp. 4930-4937 ◽  
Author(s):  
Arnold S. Bayer ◽  
Nagendra N. Mishra ◽  
Liang Chen ◽  
Barry N. Kreiswirth ◽  
Aileen Rubio ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Single Nucleotide Polymorphisms ◽  
Surface Charge ◽  
Host Defense ◽  
Cross Resistance ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Methicillin Resistant ◽  
Content Type ◽  
Positive Surface Charge

ABSTRACTMprF is responsible for the lysinylation of phosphatidylglycerol (PG) to synthesize the positively charged phospholipid (PL) species, lysyl-PG (L-PG). It has been proposed that the single-nucleotide polymorphisms (SNPs) within themprFopen reading frame (ORF) are associated with a gain-in-function phenotype in terms of daptomycin resistance inStaphylococcus aureus. (Note that although the official term is daptomycin nonsusceptibility, we use the term daptomycin resistance in this paper for ease of presentation.) Using 22 daptomycin-susceptible (DAPs)/daptomycin-resistant (DAPr) clinical methicillin-resistantS. aureus(MRSA) strain pairs, we assessed (i) the frequencies and distribution of putativemprFgain-in-function SNPs, (ii) the relationships of the SNPs to both daptomycin resistance and cross-resistance to the prototypical endovascular host defense peptide (HDP) thrombin-induced platelet microbicidal protein (tPMP), and (iii) the impact ofmprFSNPs on positive surface charge phenotype and modifications of membrane PL profiles. Most of themprFSNPs identified in our DAPrstrains were clustered within the two MprF loci, (i) the central bifunctional domain and (ii) the C-terminal synthase domain. Moreover, we were able to correlate the presence and location ofmprFSNPs in DAPrstrains with HDP cross-resistance, positive surface charge, and L-PG profiles. Although DAPrstrains withmprFSNPs in the bifunctional domain showed higher resistance to tPMPs than DAPrstrains with SNPs in the synthase domain, this relationship was not observed in positive surface charge assays. These results demonstrated that both charge-mediated and -unrelated mechanisms are involved in DAP resistance and HDP cross-resistance inS. aureus.

scholarly journals Association between Type AblaZGene Polymorphism and Cefazolin Inoculum Effect in Methicillin-Susceptible Staphylococcus aureus

2016 ◽  
Vol 60 (11) ◽  
pp. 6928-6932 ◽  
Author(s):  
Sun Hee Lee ◽  
Wan Beom Park ◽  
Shinwon Lee ◽  
Sohee Park ◽  
Shin Woo Kim ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Amino Acid ◽  
Single Nucleotide Polymorphisms ◽  
Amino Acid Sequence ◽  
Type A ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Inoculum Concentration ◽  
Content Type ◽  
Inoculum Effect

ABSTRACTSome proportion of type AblaZgene-positive methicillin-susceptibleStaphylococcus aureusstrains exhibit the cefazolin inoculum effect (CIE). The type AblaZgene was divided into two groups by single nucleotide polymorphisms (SNPs) at Ser226Pro and Cys229Tyr. The median cefazolin MICs at a high inoculum concentration were 5.69 μg/ml for the Ser-Cys group and 40.32 μg/ml for the Pro-Tyr group (P= 0.01). The SNPs at codons 226 and 229 in the amino acid sequence encoded by theblaZgene were closely associated with the CIE.

scholarly journals The role of 25-hydroxyvitamin-D3 and vitamin D receptor gene in human periodontal ligament fibroblasts as response to orthodontic compressive strain: an in vitro study

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Erika Calvano Küchler ◽  
Agnes Schröder ◽  
Vinicius Broska Teodoro ◽  
Ute Nazet ◽  
Rafaela Scariot ◽  
...  
Keyword(s):  
Gene Expression ◽  
Vitamin D ◽  
Single Nucleotide Polymorphisms ◽  
Periodontal Ligament ◽  
Compressive Strain ◽  
Nucleotide Polymorphisms ◽  
Periodontal Ligament Fibroblasts ◽  
Single Nucleotide ◽  
Cox 2

Abstract Background This study aimed to investigate, if different physiological concentrations of vitamin D (25(OH)D3) and single nucleotide polymorphisms in vitamin D receptor (VDR) gene have an impact on gene expression in human periodontal ligament (hPDL) fibroblasts induced by simulated orthodontic compressive strain. Methods A pool of hPDL fibroblasts was treated in absence or presence of 25(OH)D3 in 3 different concentrations (10, 40 and 60 ng/ml). In order to evaluate the role of single nucleotide polymorphisms in the VDR gene, hPDL fibroblasts from 9 patients were used and treated in absence or presence of 40 ng/ml 25(OH)D3. Each experiment was performed with and without simulated orthodontic compressive strain. Real-time PCR was used for gene expression and allelic discrimination analysis. Relative expression of dehydrocholesterol reductase (DHCR7), Sec23 homolog A, amidohydrolase domain containing 1 (AMDHD1), vitamin D 25-hydroxylase (CYP2R1), Hydroxyvitamin D-1-α hydroxylase, receptor activator of nuclear factor-κB ligand (RANKL), osteoprotegerin (OPG), cyclooxygenase-2 (COX-2) and interleukin-6 (IL6) was assessed. Three single nucleotide polymorphisms in VDR were genotyped. Parametric or non-parametric tests were used with an alpha of 5%. Results RANKL, RANKL:OPG ratio, COX-2, IL-6, DHCR7, CYP2R1 and AMDHD1 were differentially expressed during simulated orthodontic compressive strain (p < 0.05). The RANKL:OPG ratio was downregulated by all concentrations (10 ng/ml, 40 ng/ml and 60 ng/ml) of 25(OH)D3 (mean = 0.96 ± 0.68, mean = 1.61 ± 0.66 and mean = 1.86 ± 0.78, respectively) in comparison to the control (mean 2.58 ± 1.16) (p < 0.05). CYP2R1 gene expression was statistically modulated by the different 25(OH)D3 concentrations applied (p = 0.008). Samples from individuals carrying the GG genotype in rs739837 presented lower VDR mRNA expression and samples from individuals carrying the CC genotype in rs7975232 presented higher VDR mRNA expression (p < 0.05). Conclusions Simulated orthodontic compressive strain and physiological concentrations of 25(OH)D3 seem to regulate the expression of orthodontic tooth movement and vitamin-D-related genes in periodontal ligament fibroblasts in the context of orthodontic compressive strain. Our study also suggests that single nucleotide polymorphisms in the VDR gene regulate VDR expression in periodontal ligament fibroblasts in the context of orthodontic compressive strain.

Associations between varied susceptibilities of PfATP4 inhibitors and genotypes in Ugandan Plasmodium falciparum isolates

2021 ◽  
Author(s):  
Oriana Kreutzfeld ◽  
Stephanie A. Rasmussen ◽  
Aarti A. Ramanathan ◽  
Patrick K. Tumwebaze ◽  
Oswald Byaruhanga ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Single Nucleotide Polymorphisms ◽  
Ex Vivo ◽  
Nucleotide Polymorphisms ◽  
Wild Type ◽  
Single Nucleotide ◽  
Field Isolates ◽  
Frequent Mutations ◽  
Mixed Field ◽  
P Type

Among novel compounds under recent investigation as potential new antimalarial drugs are three independently developed inhibitors of the Plasmodium falciparum P-type ATPase (PfATP4): KAE609 (cipargamin), PA92, and SJ733. We assessed ex vivo susceptibilities to these compounds of 374 fresh P. falciparum isolates collected in Tororo and Busia districts, Uganda from 2016-2019. Median IC 50 s were 65 nM for SJ733, 9.1 nM for PA92, and 0.5 nM for KAE609. Sequencing of pfatp4 for 218 of these isolates demonstrated many non-synonymous single nucleotide polymorphisms; the most frequent mutations were G1128R (69% of isolates mixed or mutant), Q1081K/R (68%), G223S (25%), N1045K (16%) and D1116G/N/Y (16%). The G223S mutation was associated with decreased susceptibility to SJ733, PA92 and KAE609. The D1116G/N/Y mutations were associated with decreased susceptibility to SJ733, and the presence of mutations at both codons 223 and 1116 was associated with decreased susceptibility to PA92 and SJ733. In all of these cases, absolute differences in susceptibilities of wild type (WT) and mutant parasites were modest. Analysis of clones separated from mixed field isolates consistently identified mutant clones as less susceptible than WT. Analysis of isolates from other sites demonstrated presence of the G223S and D1116G/N/Y mutations across Uganda. Our results indicate that malaria parasites circulating in Uganda have a number of polymorphisms in PfATP4 and that modestly decreased susceptibility to PfATP4 inhibitors is associated with some mutations now present in Ugandan parasites.

Clinical outcome of patients with follicular lymphoma receiving chemoimmunotherapy in the PRIMA study is not affected by FCGR3A and FCGR2A polymorphisms

Blood ◽  
2012 ◽  
Vol 120 (13) ◽  
pp. 2650-2657 ◽  
Author(s):  
Hervé Ghesquières ◽  
Guillaume Cartron ◽  
John Francis Seymour ◽  
Marie-Hélène Delfau-Larue ◽  
Fritz Offner ◽  
...  
Keyword(s):  
Single Nucleotide Polymorphisms ◽  
Follicular Lymphoma ◽  
Response Rate ◽  
Single Agent ◽  
Progression Free Survival ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Free Survival ◽  
Rituximab Maintenance

Abstract In patients with follicular lymphoma treated with single-agent rituximab, single nucleotide polymorphisms in the FCGR3A gene are known to influence response and progression-free survival. The prognostic role of FCGR3A and FCGR2A polymorphisms in patients with follicular lymphoma treated with rituximab and chemotherapy combination remains controversial and has not been evaluated in the context of rituximab maintenance. FCGR3A and FCGR2A single nucleotide polymorphisms were evaluated in, respectively, 460 and 455 patients treated in the PRIMA study to investigate whether these were associated with response rate and patient outcome after rituximab chemotherapy induction and 2-year rituximab maintenance. In this representative patient cohort, complete and unconfirmed complete responses after rituximab chemotherapy were observed in 65%, 67%, 66% (P = .86) and 60%, 72%, 66% (P = .21) of FCGR3A VV, VF, FF and FCGR2A HH, HR, RR carriers, respectively. After 2 years of rituximab maintenance (or observation), response rates did not differ among the different genotypes. Progression-free survival measured from either treatment initiation or randomization to observation or maintenance was not influenced by these polymorphisms. These data indicate that FCGR3A and FCGR2A polymorphisms do not influence response rate and outcome when rituximab is combined with chemotherapy or used as maintenance treatment. The PRIMA study is registered at www.clinicaltrials.gov as NCT00140582.

scholarly journals Identification of Single Nucleotide Polymorphisms Associated with Hyperproduction of Alpha-Toxin in Staphylococcus aureus

PLoS ONE ◽  
2011 ◽  
Vol 6 (4) ◽  
pp. e18428 ◽  
Author(s):  
Xudong Liang ◽  
Jeffrey W. Hall ◽  
Junshu Yang ◽  
Meiying Yan ◽  
Katherine Doll ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Single Nucleotide Polymorphisms ◽  
Nucleotide Polymorphisms ◽  
Alpha Toxin ◽  
Single Nucleotide

An Updated Review on the Role of Single Nucleotide Polymorphisms in COVID-19 Disease Severity: A Global Aspect

2022 ◽  
Vol 23 ◽  
Author(s):  
Jun Wei Ng ◽  
Eric Tzyy Jiann Chong ◽  
Ping-Chin Lee
Keyword(s):  
Single Nucleotide Polymorphisms ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Angiotensin Converting Enzyme 2 ◽  
Global Pandemic ◽  
Global Aspect ◽  
Common Risk Factors ◽  
Severity Of The Disease ◽  
Ace2 Gene

Abstract: Coronavirus disease 2019 (COVID-19) is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and recently has become a serious global pandemic. Age, gender, and comorbidities are known to be common risk factors for severe COVID-19 but are not enough to fully explain the magnitude of their effect on the risk of severity of the disease. Single nucleotide polymorphisms (SNPs) in several genes have been reported as a genetic factor contributing to COVID-19 severity. This comprehensive review focuses on the association between SNPs in four important genes and COVID-19 severity in a global aspect. We discuss a total of 39 SNPs in this review: five SNPs in the ABO gene, nine SNPs in the angiotensin-converting enzyme 2 (ACE2) gene, 19 SNPs in the transmembrane protease serine 2 (TMPRSS2) gene, and six SNPs in the toll-like receptor 7 (TLR7) gene. These SNPs data could assist in monitoring an individual's risk of severe COVID-19 disease, and therefore personalized management and pharmaceutical treatment could be planned in COVID-19 patients.

scholarly journals Using Mycobacterium tuberculosis Single-Nucleotide Polymorphisms To Predict Fluoroquinolone Treatment Response

2019 ◽  
Vol 63 (7) ◽  
Author(s):  
Marva Seifert ◽  
Edmund Capparelli ◽  
Donald G. Catanzaro ◽  
Timothy C. Rodwell
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Single Nucleotide Polymorphisms ◽  
Specific Resistance ◽  
Therapeutic Targets ◽  
World Health ◽  
Population Pharmacokinetic ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Content Type ◽  
Level Increase

ABSTRACT Clinical phenotypic fluoroquinolone susceptibility testing of Mycobacterium tuberculosis is currently based on M. tuberculosis growth at a single critical concentration, which provides limited information for a nuanced clinical response. We propose using specific resistance-conferring M. tuberculosis mutations in gyrA together with population pharmacokinetic and pharmacodynamic modeling as a novel tool to better inform fluoroquinolone treatment decisions. We sequenced the gyrA resistance-determining region of 138 clinical M. tuberculosis isolates collected from India, Moldova, Philippines, and South Africa and then determined each strain’s MIC against ofloxacin, moxifloxacin, levofloxacin, and gatifloxacin. Strains with specific gyrA single-nucleotide polymorphisms (SNPs) were grouped into high or low drug-specific resistance categories based on their empirically measured MICs. Published population pharmacokinetic models were then used to explore the pharmacokinetics and pharmacodynamics of each fluoroquinolone relative to the empirical MIC distribution for each resistance category to make predictions about the likelihood of patients achieving defined therapeutic targets. In patients infected with M. tuberculosis isolates containing SNPs associated with a fluoroquinolone-specific low-level increase in MIC, models suggest increased fluoroquinolone dosing improved the probability of achieving therapeutic targets for gatifloxacin and moxifloxacin but not for levofloxacin and ofloxacin. In contrast, among patients with isolates harboring SNPs associated with a high-level increase in MIC, increased dosing of levofloxacin, moxifloxacin, gatifloxacin, or ofloxacin did not meaningfully improve the probability of therapeutic target attainment. We demonstrated that quantifiable fluoroquinolone drug resistance phenotypes could be predicted from rapidly detectable gyrA SNPs and used to support dosing decisions based on the likelihood of patients reaching therapeutic targets. Our findings provide further supporting evidence for the moxifloxacin clinical breakpoint recently established by the World Health Organization.

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