scholarly journals A Naturally Occurring Proline-to-Alanine Amino Acid Change in Fks1p in Candida parapsilosis, Candida orthopsilosis, and Candida metapsilosis Accounts for Reduced Echinocandin Susceptibility

2008 ◽  
Vol 52 (7) ◽  
pp. 2305-2312 ◽  
Author(s):  
Guillermo Garcia-Effron ◽  
Santosh K. Katiyar ◽  
Steven Park ◽  
Thomas D. Edlind ◽  
David S. Perlin
Keyword(s):  
Amino Acid ◽  
Candida Parapsilosis ◽  
Hot Spot ◽  
Amino Acid Position ◽  
Intrinsic Resistance ◽  
Glucan Synthase ◽  
Equivalent Position ◽  
Naturally Occurring ◽  
Candida Metapsilosis ◽  
Candida Orthopsilosis

ABSTRACT Candida parapsilosis has emerged as a common cause of invasive fungal infection, especially in Latin America and in the neonatal setting. C. parapsilosis is part of a closely related group of organisms that includes the species Candida orthopsilosis and Candida metapsilosis. All three species show elevated MICs for the new echinocandin class drugs caspofungin, micafungin, and anidulafungin relative to other Candida species. Despite potential impacts on therapy, the mechanism behind this reduced echinocandin susceptibility has not been determined. In this report, we investigated the role of a naturally occurring Pro-to-Ala substitution at amino acid position 660 (P660A), immediately distal to the highly conserved hot spot 1 region of Fks1p, in the reduced-echinocandin-susceptibility phenotype. Kinetic inhibition studies demonstrated that glucan synthase from the C. parapsilosis group was 1 to 2 logs less sensitive to echinocandin drugs than the reference enzyme from C. albicans. Furthermore, clinical isolates of C. albicans and C. glabrata which harbor mutations at this equivalent position also showed comparable 2-log decreases in target enzyme sensitivity, which correlated with increased MICs. These mutations also resulted in 2.4- to 18.8-fold-reduced V max values relative to those for the wild-type enzyme, consistent with kinetic parameters obtained for C. parapsilosis group enzymes. Finally, the importance of the P660A substitution for intrinsic resistance was confirmed by engineering an equivalent P647A mutation into Fks1p of Saccharomyces cerevisiae. The mutant glucan synthase displayed characteristic 2-log decreases in sensitivity to the echinocandin drugs. Overall, these data firmly indicate that a naturally occurring P660A substitution in Fks1p from the C. parapsilosis group accounts for the reduced susceptibility phenotype.

scholarly journals A case series of medically managed Candida parapsilosis complex prosthetic valve endocarditis

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Penghao Guo ◽  
Yuting He ◽  
Rui Fan ◽  
Zhongwen Wu ◽  
Yili Chen ◽  
...  
Keyword(s):  
Prosthetic Valve ◽  
Candida Parapsilosis ◽  
Case Series ◽  
Prosthetic Valve Endocarditis ◽  
Sensu Stricto ◽  
Maldi Tof Ms ◽  
Maldi Tof ◽  
Candida Metapsilosis ◽  
Candida Orthopsilosis ◽  
Tof Ms

Abstract Background In recent years, Candida parapsilosis is recognized as a species complex and is composed of Candida parapsilosis sensu stricto, Candida orthopsilosis and Candida metapsilosis. Candida parapsilosis complex prosthetic valve endocarditis (PVE) is rare and the survival rate is still low despite of optimal therapeutic strategies. In our report, it is novel to report cases as Candida parapsilosis complex PVE at species and identify Candida parapsilosis using MALDI-TOF MS. Case presentation A series of 4 cases of Candida parapsilosis complex PVE from our institution was reported. Three were infected by Candida parapsilosis sensu stricto and one was infected by Candida metapsilosis. The condition of two cases got better and the other died. Conclusions More attention should be paid to Candida parapsilosis complex PVE and early diagnosis and prompt antibiotic therapy may play a role in the treatment for Candida parapsilosis complex PVE. It is recommended to identify Candida parapsilosis complex at species level and MALDI-TOF MS as an easy, fast and efficient identification method is worth promoting in clinical microbiology

scholarly journals Prevalence, distribution and antifungal susceptibility profiles of Candida parapsilosis, Candida orthopsilosis and Candida metapsilosis bloodstream isolates

2012 ◽  
Vol 61 (7) ◽  
pp. 1003-1008 ◽  
Author(s):  
Lucas Xavier Bonfietti ◽  
Marilena dos Anjos Martins ◽  
Maria Walderez Szeszs ◽  
Sandra Brasil Stolf Pukiskas ◽  
Sonia Ueda Purisco ◽  
...  
Keyword(s):  
Candida Parapsilosis ◽  
Antifungal Susceptibility ◽  
Candida Metapsilosis ◽  
Candida Orthopsilosis ◽  
Susceptibility Profiles

scholarly journals Prevalence and Susceptibility Profile of Candida metapsilosis and Candida orthopsilosis: Results from Population-Based Surveillance of Candidemia in Spain

2008 ◽  
Vol 52 (4) ◽  
pp. 1506-1509 ◽  
Author(s):  
A. Gomez-Lopez ◽  
A. Alastruey-Izquierdo ◽  
D. Rodriguez ◽  
B. Almirante ◽  
A. Pahissa ◽  
...  
Keyword(s):  
Candida Parapsilosis ◽  
Population Based ◽  
Candida Metapsilosis ◽  
Candida Orthopsilosis ◽  
Susceptibility Profiles

ABSTRACT We describe the prevalences and susceptibility profiles of two recently described species, Candida metapsilosis and Candida orthopsilosis, related to Candida parapsilosis in candidemia. The prevalences of these species (1.7% for C. metapsilosis and 1.4% for C. orthopsilosis) are significant. Differences observed in their susceptibility profiles could have therapeutic importance.

scholarly journals A Naturally Occurring Rgg Variant in Serotype M3 Streptococcus pyogenes Does Not Activate speB Expression Due to Altered Specificity of DNA Binding

2009 ◽  
Vol 77 (12) ◽  
pp. 5411-5417 ◽  
Author(s):  
Kyle V. Kappeler ◽  
Srivishnupriya Anbalagan ◽  
Alexander V. Dmitriev ◽  
Emily J. McDowell ◽  
Melody N. Neely ◽  
...  
Keyword(s):  
Amino Acid ◽  
Streptococcus Pyogenes ◽  
Murine Model ◽  
Cysteine Protease ◽  
Phenotypic Diversity ◽  
Transcriptional Regulator ◽  
Amino Acid Position ◽  
Invasive Disease ◽  
Naturally Occurring

ABSTRACT The transcriptional regulator Rgg of Streptococcus pyogenes is essential for expression of the secreted cysteine protease SpeB. Although all isolates of S. pyogenes possess the speB gene, not all of them produce the protein in vitro. In a murine model of infection, the absence of SpeB production is associated with invasive disease. We speculated that naturally occurring mutations in rgg, which would also abrogate SpeB production, may be present in invasive isolates of S. pyogenes. Examination of the inferred Rgg sequences available in public databases revealed that the rgg gene in strain MGAS315 (a serotype M3 strain associated with invasive disease) encodes a proline at amino acid position 103 (Rgg103P); in contrast, all other strains encode a serine at this position (Rgg103S). A caseinolytic assay and Western blotting indicated that strain MGAS315 does not produce SpeB in vitro. Gene-swapping experiments showed that the rgg gene of MGAS315 is solely responsible for the lack of SpeB expression. In contrast to Rgg103S, Rgg103P does not bind to the speB promoter in gel shift assays, which correlates with a lack of speB expression. Despite its inability to activate speB expression, Rgg103P retains the ability to bind to DNA upstream of norA and to influence its expression. Overall, this study illustrates how variation at the rgg locus may contribute to the phenotypic diversity of S. pyogenes.

scholarly journals HIV-1 Protease, Reverse Transcriptase, and Integrase Variation

2016 ◽  
Vol 90 (13) ◽  
pp. 6058-6070 ◽  
Author(s):  
Soo-Yon Rhee ◽  
Kris Sankaran ◽  
Vici Varghese ◽  
Mark A. Winters ◽  
Christopher B. Hurt ◽  
...  
Keyword(s):  
Quality Control ◽  
Amino Acid ◽  
Amino Acid Position ◽  
Antiretroviral Drugs ◽  
Resistance Testing ◽  
Genotypic Resistance ◽  
Naturally Occurring ◽  
Genotypic Resistance Testing ◽  
Hiv 1 ◽  
Amino Acid Variants

ABSTRACTHIV-1 protease (PR), reverse transcriptase (RT), and integrase (IN) variability presents a challenge to laboratories performing genotypic resistance testing. This challenge will grow with increased sequencing of samples enriched for proviral DNA such as dried blood spots and increased use of next-generation sequencing (NGS) to detect low-abundance HIV-1 variants. We analyzed PR and RT sequences from >100,000 individuals and IN sequences from >10,000 individuals to characterize variation at each amino acid position, identify mutations indicating APOBEC-mediated G-to-A editing, and identify mutations resulting from selective drug pressure. Forty-seven percent of PR, 37% of RT, and 34% of IN positions had one or more amino acid variants with a prevalence of ≥1%. Seventy percent of PR, 60% of RT, and 60% of IN positions had one or more variants with a prevalence of ≥0.1%. Overall 201 PR, 636 RT, and 346 IN variants had a prevalence of ≥0.1%. The median intersubtype prevalence ratios were 2.9-, 2.1-, and 1.9-fold for these PR, RT, and IN variants, respectively. Only 5.0% of PR, 3.7% of RT, and 2.0% of IN variants had a median intersubtype prevalence ratio of ≥10-fold. Variants at lower prevalences were more likely to differ biochemically and to be part of an electrophoretic mixture compared to high-prevalence variants. There were 209 mutations indicative of APOBEC-mediated G-to-A editing and 326 mutations nonpolymorphic treatment selected. Identification of viruses with a high number of APOBEC-associated mutations will facilitate the quality control of dried blood spot sequencing. Identifying sequences with a high proportion of rare mutations will facilitate the quality control of NGS.IMPORTANCEMost antiretroviral drugs target three HIV-1 proteins: PR, RT, and IN. These proteins are highly variable: many different amino acids can be present at the same position in viruses from different individuals. Some of the amino acid variants cause drug resistance and occur mainly in individuals receiving antiretroviral drugs. Some variants result from a human cellular defense mechanism called APOBEC-mediated hypermutation. Many variants result from naturally occurring mutation. Some variants may represent technical artifacts. We studied PR and RT sequences from >100,000 individuals and IN sequences from >10,000 individuals to quantify variation at each amino acid position in these three HIV-1 proteins. We performed analyses to determine which amino acid variants resulted from antiretroviral drug selection pressure, APOBEC-mediated editing, and naturally occurring variation. Our results provide information essential to clinical, research, and public health laboratories performing genotypic resistance testing by sequencing HIV-1 PR, RT, and IN.

scholarly journals Echinocandin-Induced Microevolution of Candida parapsilosis Influences Virulence and Abiotic Stress Tolerance

mSphere ◽  
2018 ◽  
Vol 3 (6) ◽  
Author(s):  
Csaba Papp ◽  
Katica Kocsis ◽  
Renáta Tóth ◽  
László Bodai ◽  
Jesse R. Willis ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Amino Acid ◽  
Candida Parapsilosis ◽  
Hot Spot ◽  
Abiotic Stress Tolerance ◽  
Acquired Resistance ◽  
Cross Resistance ◽  
First Line ◽  
Content Type

ABSTRACT Candida species are a major cause of life-threatening bloodstream infections worldwide. Although Candida albicans is responsible for the vast majority of infections, the clinical relevance of other Candida species has also emerged over the last twenty years. This shift might be due in part to changes in clinical guidelines, as echinocandins became the first line of therapeutics for the treatment. Candida parapsilosis is an emerging non-albicans Candida species that exhibits lower susceptibility levels to these drugs. Candida species frequently display resistance to echinocandins, and the mechanism for this is well-known in C. albicans and Candida glabrata, where it is mediated by amino acid substitutions at defined locations of the β-1,3-glucan synthase, Fks1p. In C. parapsilosis isolates, Fks1p harbors an intrinsic amino acid change at position 660 of the hot spot 1 (HS1) region, which is thought to be responsible for the high MIC values. Less is known about acquired substitutions in this species. In this study, we used directed evolution experiments to generate C. parapsilosis strains with acquired resistance to caspofungin, anidulafungin, and micafungin. We showed that cross-resistance was dependent on the type of echinocandin used to generate the evolved strains. During their characterization, all mutant strains showed attenuated virulence in vivo and also displayed alterations in the exposure of inner cell wall components. The evolved strains harbored 251 amino acid changes, including three in the HS1, HS2, and HS3 regions of Fks1p. Altogether, our results demonstrate a direct connection between acquired antifungal resistance and virulence of C. parapsilosis. IMPORTANCE Candida parapsilosis is an opportunistic fungal pathogen with the ability to cause infections in immunocompromised patients. Echinocandins are the currently recommended first line of treatment for all Candida species. Resistance of Candida albicans to this drug type is well characterized. C. parapsilosis strains have the lowest in vitro susceptibility to echinocandins; however, patients with such infections typically respond well to echinocandin therapy. There is little knowledge of acquired resistance in C. parapsilosis and its consequences on other characteristics such as virulence properties. In this study, we aimed to dissect how acquired echinocandin resistance influences the pathogenicity of C. parapsilosis and to develop explanations for why echinocandins are clinically effective in the setting of acquired resistance.

Virulence of Candida parapsilosis, Candida orthopsilosis, and Candida metapsilosis in reconstituted human tissue models

2007 ◽  
Vol 44 (12) ◽  
pp. 1336-1341 ◽  
Author(s):  
Attila Gácser ◽  
Wilhelm Schäfer ◽  
Jerome S. Nosanchuk ◽  
Siegfried Salomon ◽  
Joshua D. Nosanchuk
Keyword(s):  
Human Tissue ◽  
Candida Parapsilosis ◽  
Candida Metapsilosis ◽  
Candida Orthopsilosis ◽  
Tissue Models
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