scholarly journals Comparative Pathogenicity of United Kingdom Isolates of the Emerging Pathogen Candida auris and Other Key Pathogenic Candida Species

mSphere ◽  
2016 ◽  
Vol 1 (4) ◽  
Author(s):  
Andrew M. Borman ◽  
Adrien Szekely ◽  
Elizabeth M. Johnson
Keyword(s):  
Invasive Candidiasis ◽  
Fungal Pathogen ◽  
Galleria Mellonella ◽  
Systemic Infection ◽  
Mortality Rates ◽  
Infection Model ◽  
Candida Auris ◽  
Deep Tissue ◽  
Content Type

ABSTRACT The incidence of invasive candidiasis, which includes candidemia and deep tissue infections, continues to rise and is associated with considerable mortality rates. Candida albicans remains the most common cause of invasive candidiasis, although the prevalence of non-albicans species has increased over recent years. Since its first description in 2009, Candida auris has emerged as a serious nosocomial health risk, with widespread outbreaks in numerous hospitals worldwide. However, despite receiving considerable attention, little is known concerning the pathogenicity of this emerging fungal pathogen. Here, using the Galleria mellonella insect systemic infection model, we show strain-specific differences in the virulence of C. auris, with the most virulent isolates exhibiting pathogenicity comparable to that of C. albicans, which is currently accepted as the most pathogenic member of the genus. Candida auris, first described in 2009, has since emerged as an important, multidrug-resistant, nosocomial agent of candidemia, with large outbreaks reported worldwide and high mortality rates associated with therapeutic failure. The current study employed C. auris isolates from a variety of centers in the United Kingdom to evaluate the pathogenicity of this emerging pathogen compared to that of other common pathogenic yeast species in the invertebrate Galleria mellonella infection model. We showed that C. auris isolates differ in their growth characteristics in vitro, with a proportion of isolates failing to release daughter cells after budding, resulting in the formation of large aggregates of cells that cannot be physically disrupted. Our results also demonstrate strain-specific differences in the behavior of C. auris in G. mellonella, with the aggregate-forming isolates exhibiting significantly less pathogenicity than their nonaggregating counterparts. Importantly, the nonaggregating isolates exhibited pathogenicity comparable to that of C. albicans, which is currently accepted as the most pathogenic member of the genus, despite the fact that C. auris isolates do not produce hyphae and produce only rudimentary pseudohyphae either in vitro or in G. mellonella. IMPORTANCE The incidence of invasive candidiasis, which includes candidemia and deep tissue infections, continues to rise and is associated with considerable mortality rates. Candida albicans remains the most common cause of invasive candidiasis, although the prevalence of non-albicans species has increased over recent years. Since its first description in 2009, Candida auris has emerged as a serious nosocomial health risk, with widespread outbreaks in numerous hospitals worldwide. However, despite receiving considerable attention, little is known concerning the pathogenicity of this emerging fungal pathogen. Here, using the Galleria mellonella insect systemic infection model, we show strain-specific differences in the virulence of C. auris, with the most virulent isolates exhibiting pathogenicity comparable to that of C. albicans, which is currently accepted as the most pathogenic member of the genus.

scholarly journals Chitosan Ameliorates Candida auris Virulence in a Galleria mellonella Infection Model

2020 ◽  
Vol 64 (8) ◽  
Author(s):  
Laís Salomão Arias ◽  
Mark C. Butcher ◽  
Bryn Short ◽  
Emily McKloud ◽  
Chris Delaney ◽  
...  
Keyword(s):  
Galleria Mellonella ◽  
Survival Rates ◽  
Health Care Facilities ◽  
Antifungal Drugs ◽  
Infection Model ◽  
Candida Auris ◽  
Gene Expression Response ◽  
Content Type

ABSTRACT Candida auris has emerged as a multidrug-resistant nosocomial pathogen over the last decade. Outbreaks of the organism in health care facilities have resulted in life-threatening invasive candidiasis in over 40 countries worldwide. Resistance by C. auris to conventional antifungal drugs such as fluconazole and amphotericin B means that alternative therapeutics must be explored. As such, this study served to investigate the efficacy of a naturally derived polysaccharide called chitosan against aggregative (Agg) and nonaggregative (non-Agg) isolates of C. auris in vitro and in vivo. In vitro results indicated that chitosan was effective against planktonic and sessile forms of Agg and non-Agg C. auris. In a Galleria mellonella model to assess C. auris virulence, chitosan treatment was shown to ameliorate killing effects of both C. auris phenotypes (NCPF 8973 and NCPF 8978, respectively) in vivo. Specifically, chitosan reduced the fungal load and increased survival rates of infected Galleria, while treatment alone was nontoxic to the larvae. Finally, chitosan treatment appeared to induce a stress-like gene expression response in NCPF 8973 in the larvae likely arising from a protective response by the organism to resist antifungal activity of the compound. Taken together, results from this study demonstrate that naturally derived compounds such as chitosan may be useful alternatives to conventional antifungals against C. auris.

scholarly journals Activity of Telavancin against Staphylococcus aureus Isolates, Including Those with Decreased Susceptibility to Ceftaroline, from Cystic Fibrosis Patients

2018 ◽  
Vol 62 (9) ◽  
Author(s):  
Melanie Roch ◽  
Maria Celeste Varela ◽  
Agustina Taglialegna ◽  
Warren E. Rose ◽  
Adriana E. Rosato
Keyword(s):  
Cystic Fibrosis ◽  
Staphylococcus Aureus ◽  
Galleria Mellonella ◽  
Therapeutic Option ◽  
The United States ◽  
Infection Model ◽  
Content Type ◽  
Complicated Skin ◽  
Hospital Acquired

ABSTRACT Methicillin-resistant Staphylococcus aureus (MRSA) acquisition in cystic fibrosis (CF) patients confers a clinical outcome worse than that in non-CF patients with an increased rate of declined lung function. Telavancin, an approved lipoglycopeptide used to treat infections due to S. aureus, has a dual mode of action causing inhibition of peptidoglycan synthesis and membrane depolarization. MRSA infections in CF patients remain an important problem with no foreseeable decline in prevalence rates. Although telavancin is currently in clinical use for the treatment of complicated skin infections and hospital-acquired pneumonia, the activity against S. aureus infections in CF patients has not been investigated. In this work, we studied the activity of telavancin against CF patient-derived S. aureus strains collected from geographically diverse CF centers in the United States. We found that the telavancin MIC90 was 0.06 μg/ml, 8-fold lower than the ceftaroline or daptomycin MIC90 and 25-fold lower than the linezolid and vancomycin MIC90. We demonstrate that telavancin at serum free concentrations has rapid bactericidal activity, with a decrease of more than 3 log10 CFU/ml being achieved during the first 4 to 6 h of treatment, performing better in this assay than vancomycin and ceftaroline, including against S. aureus strains resistant to ceftaroline. Telavancin resistance was infrequent (0.3%), although we found that it can occur in vitro in both CF- and non-CF patient-derived S. aureus strains by progressive passages with subinhibitory concentrations. Genetic analysis of telavancin-resistant in vitro mutants showed gene polymorphisms in cell wall and virulence genes and increased survival in a Galleria mellonella infection model. Thus, we conclude that telavancin represents a promising therapeutic option for infections in CF patients with potent in vitro activity and a low resistance development potential.

scholarly journals YraP Contributes to Cell Envelope Integrity and Virulence ofSalmonella entericaSerovar Typhimurium

2018 ◽  
Vol 86 (11) ◽  
Author(s):  
Faye C. Morris ◽  
Timothy J. Wells ◽  
Jack A. Bryant ◽  
Anna E. Schager ◽  
Yanina R. Sevastsyanovich ◽  
...  
Keyword(s):  
Outer Membrane ◽  
Cell Envelope ◽  
Systemic Infection ◽  
Eukaryotic Cell ◽  
Infection Model ◽  
Content Type ◽  
Protein Levels ◽  
K 12

ABSTRACTMutations in σE-regulated lipoproteins have previously been shown to impact bacterial viability under conditions of stress and duringin vivoinfection. YraP is conserved across a number of Gram-negative pathogens, includingNeisseria meningitidis, where the homolog is a component of the Bexsero meningococcal group B vaccine. Investigations using laboratory-adaptedEscherichia coliK-12 have shown thatyraPmutants have elevated sensitivity to a range of compounds, including detergents and normally ineffective antibiotics. In this study, we investigate the role of the outer membrane lipoprotein YraP in the pathogenesis ofSalmonella entericaserovar Typhimurium. We show that mutations inS. TyphimuriumyraPresult in a defective outer membrane barrier with elevated sensitivity to a range of compounds. This defect is associated with attenuated virulence in an oral infection model and during the early stages of systemic infection. We show that this attenuation is not a result of defects in lipopolysaccharide and O-antigen synthesis, changes in outer membrane protein levels, or the ability to adhere to and invade eukaryotic cell linesin vitro.

scholarly journals Pancreatic Amylase Is an Environmental Signal for Regulation of Biofilm Formation and Host Interaction in Campylobacter jejuni

2015 ◽  
Vol 83 (12) ◽  
pp. 4884-4895 ◽  
Author(s):  
Waheed Jowiya ◽  
Katja Brunner ◽  
Sherif Abouelhadid ◽  
Haitham A. Hussain ◽  
Sean P. Nair ◽  
...  
Keyword(s):  
Campylobacter Jejuni ◽  
Biofilm Formation ◽  
Galleria Mellonella ◽  
Infection Model ◽  
Pancreatic Amylase ◽  
Content Type ◽  
Host Interaction ◽  
Food Borne ◽  
Epithelial Cell Lines

Campylobacter jejuniis a commensal bacterium in the intestines of animals and birds and a major cause of food-borne gastroenteritis in humans worldwide. Here we show that exposure to pancreatic amylase leads to secretion of an α-dextran byC. jejuniand that a secreted protease, Cj0511, is required. Exposure ofC. jejunito pancreatic amylase promotes biofilm formationin vitro, increases interaction with human epithelial cell lines, increases virulence in theGalleria mellonellainfection model, and promotes colonization of the chicken ileum. We also show that exposure to pancreatic amylase protectsC. jejunifrom stress conditionsin vitro, suggesting that the induced α-dextran may be important during transmission between hosts. This is the first evidence that pancreatic amylase functions as an interkingdom signal in an enteric microorganism.

scholarly journals Emerging Fungal PathogenCandida aurisEvades Neutrophil Attack

mBio ◽  
2018 ◽  
Vol 9 (4) ◽  
Author(s):  
Chad J. Johnson ◽  
J. Muse Davis ◽  
Anna Huttenlocher ◽  
John F. Kernien ◽  
Jeniel E. Nett
Keyword(s):  
Invasive Candidiasis ◽  
Fungal Pathogen ◽  
Fungal Infections ◽  
Neutrophil Extracellular Traps ◽  
Invasive Disease ◽  
Human Neutrophils ◽  
Candida Auris ◽  
Zebrafish Model ◽  
Content Type ◽  
Extracellular Traps

ABSTRACTCandida aurishas recently emerged as the first fungal pathogen to cause a global public health threat. The reason this species is causing hospital-associated outbreaks of invasive candidiasis with high mortality is unknown. In this study, we examine the interaction ofC. auriswith neutrophils, leukocytes critical for control of invasive fungal infections. We show that human neutrophils do not effectively killC. auris. Compared toCandida albicans, neutrophils poorly recruited toC. aurisand failed to form neutrophil extracellular traps (NETs), which are structures of DNA, histones, and proteins with antimicrobial activity. In mixed cultures, neutrophils preferentially engaged and killedC. albicansoverC. auris. Imaging of neutrophils in a zebrafish larval model of invasive candidiasis revealed the recruitment of approximately 50% fewer neutrophils in response toC. auriscompared toC. albicans. Upon encounter withC. albicansin the zebrafish hindbrain, neutrophils produced clouds of histones, suggesting the formation of NETs. These structures were not observed inC. aurisinfection. Evasion of neutrophil attack and innate immunity offers an explanation for the virulence of this pathogen.IMPORTANCEThe emerging fungal pathogenCandida aurishas produced numerous outbreaks of invasive disease in hospitals worldwide. Why this species causes deadly disease is unknown. Our findings reveal a failure of neutrophils to killC. auriscompared to the most commonly encounteredCandidaspecies,C. albicans. While neutrophils produce neutrophil extracellular traps (NETs) upon encounter withC. albicans, these antimicrobial structures are not formed in response toC. auris. Using human neutrophils and a zebrafish model of invasive candidiasis, we show thatC. aurispoorly recruits neutrophils and evades immune attack. Identification of this impaired innate immune response toC. aurissheds light on the dismal outcomes for patients with invasive disease.

scholarly journals Adenylate Kinase Release as a High-Throughput-Screening-Compatible Reporter of Bacterial Lysis for Identification of Antibacterial Agents

2012 ◽  
Vol 57 (1) ◽  
pp. 26-36 ◽  
Author(s):  
Anna C. Jacobs ◽  
Louis DiDone ◽  
Jennielle Jobson ◽  
Madeline K. Sofia ◽  
Damian Krysan ◽  
...  
Keyword(s):  
Adenylate Kinase ◽  
High Throughput Screening ◽  
Antimicrobial Agents ◽  
Galleria Mellonella ◽  
Bacterial Species ◽  
Antimicrobial Properties ◽  
Infection Model ◽  
Intracellular Enzyme ◽  
Content Type

ABSTRACTAdenylate kinase (AK) is a ubiquitous intracellular enzyme that is released into the extracellular space upon cell lysis. We have shown that AK release serves as a useful reporter of bactericidal agent activity and can be exploited for antimicrobial screening purposes. The AK assay exhibits improved sensitivity over that of growth-based assays and can detect agents that are active against bacteria in clinically relevant growth states that are difficult to screen using conventional approaches, such as small colony variants (SCV) and bacteria within established biofilms. The usefulness of the AK assay was validated by screening a library of off-patent drugs for agents that exhibit antimicrobial properties toward a variety of bacterial species, includingEscherichia coliand all members of the “ESKAPE” pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacterspecies). The assay detected antibiotics within the library that were expected to be active against the organism screened. Moreover, 38 drugs with no previously reported antibacterial activity elicited AK release. Four of these were acquired, and all were verified to exhibit antimicrobial activity by standard susceptibility testing. Two of these molecules were further characterized. The antihistamine, terfenadine, was active againstS. aureusplanktonic, SCV population, and biofilm-associated cells. Tamoxifen, an estrogen receptor antagonist, was active towardE. faeciumin vitroand also reducedE. faeciumpathogenesis in aGalleria mellonellainfection model. Our data demonstrate that the AK assay provides an attractive screening approach for identifying new antimicrobial agents. Further, terfenadine and tamoxifen may represent novel antimicrobial drug development scaffolds.

scholarly journals Assessment of the In Vitro and In Vivo Antifungal Activity of NSC319726 against Candida auris

2021 ◽  
Author(s):  
Jizhou Li ◽  
Alix T. Coste ◽  
Daniel Bachmann ◽  
Dominique Sanglard ◽  
Frederic Lamoth
Keyword(s):  
Public Health ◽  
Antifungal Activity ◽  
Invasive Candidiasis ◽  
Multidrug Resistant ◽  
Candida Auris ◽  
Content Type ◽  
Health Threat ◽  
Public Health Threat

Candida auris is emerging as a major public health threat because of its ability to cause nosocomial outbreaks of severe invasive candidiasis. Management of C. auris infection is difficult because of its frequent multidrug-resistant profile for currently licensed antifungals.

scholarly journals The MUT056399 Inhibitor of FabI Is a New Antistaphylococcal Compound

2011 ◽  
Vol 55 (10) ◽  
pp. 4692-4697 ◽  
Author(s):  
S. Escaich ◽  
L. Prouvensier ◽  
M. Saccomani ◽  
L. Durant ◽  
M. Oxoby ◽  
...  
Keyword(s):  
Low Frequency ◽  
Systemic Infection ◽  
Multidrug Resistant ◽  
Infection Model ◽  
Coagulase Negative Staphylococci ◽  
Content Type ◽  
Immunocompetent Mice ◽  
Novel Drug

ABSTRACTMUT056399 is a highly potent new inhibitor of the FabI enzyme of bothStaphylococcus aureusandEscherichia coli. In vitro, MUT056399 was very active againstS. aureusstrains, including methicillin-susceptibleS. aureus(MSSA), methicillin-resistantS. aureus(MRSA), linezolid-resistant, and multidrug-resistant strains, with MIC90s between 0.03 and 0.12 μg/ml. MUT056399 was also active against coagulase-negative staphylococci, with MIC90s between 0.12 and 4 μg/ml. The antibacterial spectrum is consistent with specific FabI inhibition with no activity against bacteria using FabK but activity against FabI-containing Gram-negative bacilli.In vitro, resistant clones ofS. aureuswere obtained at a low frequency. All of the resistant clones analyzed were found to contain mutations in thefabIgene.In vivo, MUT056399, administered subcutaneously, protected mice from a lethal systemic infection induced by MSSA, MRSA, and vancomycin-intermediateS. aureusstrains (50% effective doses ranging from 19.3 mg/kg/day to 49.6 mg/kg/day). In the nonneutropenic murine thigh infection model, the same treatment with MUT056399 reduced the bacterial multiplication of MSSA and MRSA in the thighs of immunocompetent mice. These properties support MUT056399 as a very promising candidate for a novel drug to treat severe staphylococcal infections.

scholarly journals Brucella neotomaeRecapitulates Attributes of Zoonotic Human Disease in a Murine Infection Model

2018 ◽  
Vol 87 (1) ◽  
Author(s):  
Yoon-Suk Kang ◽  
Daniel A. Brown ◽  
James E. Kirby
Keyword(s):  
Cell Biology ◽  
Systemic Infection ◽  
Farm Animals ◽  
Cytokine Gene Expression ◽  
Infection Model ◽  
Content Type ◽  
Type Iv ◽  
Host Infection ◽  
Spleen And Lymph Nodes

ABSTRACTMembers of the genusBrucellaare Gram-negative pathogens that cause chronic systemic infection in farm animals and zoonotic infection in humans. Study of the genusBrucellahas been hindered by the need for biosafety level 3 select agent containment.Brucella neotomae, originally isolated from the desert pack rat, presented an opportunity to develop an alternative, non-select agent experimental model. Our priorin vitrowork indicated that the cell biology and type IV secretion system (T4SS) dependence ofB. neotomaeintracellular replication were similar to observations for human-pathogenic select agentBrucellaspecies. Therefore, here, we investigated the pathobiology ofB. neotomaeinfection in the BALB/c mouse. During a sustained infectious course,B. neotomaereplicated and persisted in reticuloendothelial organs. Bioluminescent imaging and histopathological and PCR-based analysis demonstrated that the T4SS contributed to efficient early infection of the liver, spleen, and lymph nodes; granuloma formation and hepatosplenomegaly; and early induction of Th1-associated cytokine gene expression. The infectious course and pathologies in the murine model showed similarity to prior observations of primate and native host infection with zoonoticBrucellaspecies. Therefore, theB. neotomaeBALB/c infection model offers a promising system to accelerate and complement experimental work in the genusBrucella.

scholarly journals Antibacterial Activity of a Promising Antibacterial Agent: 22-(4-(2-(4-Nitrophenyl-piperazin-1-yl)-acetyl)-piperazin-1-yl)-22-deoxypleuromutilin

Molecules ◽  
2021 ◽  
Vol 26 (12) ◽  
pp. 3502
Author(s):  
Xiang-Yi Zuo ◽  
Hong Gao ◽  
Mei-Ling Gao ◽  
Zhen Jin ◽  
You-Zhi Tang
Keyword(s):  
Antibacterial Activity ◽  
Galleria Mellonella ◽  
Systemic Infection ◽  
Effect Study ◽  
Infection Model ◽  
Oral Toxicity ◽  
Reference Drug ◽  
Antibiotic Effect

A novel pleuromutilin derivative, 22-(4-(2-(4-nitrophenyl-piperazin-1-yl)-acetyl)-piperazin-1-yl)-22-deoxypleuromutilin (NPDM), was synthesized in our laboratory and proved excellent antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA). In this study, more methods were used to further study its preliminary pharmacological effect. The antibacterial efficacy and toxicity of NPDM were evaluated using tiamulin as the reference drug. The in vitro antibacterial activity study showed that NPDM is a potent bactericidal agent against MRSA that induced time-dependent growth inhibition and a concentration-dependent post-antibiotic effect (PAE). Toxicity determination showed that the cytotoxicity of NPDM was slightly higher than that of tiamulin, but the acute oral toxicity study proved that NPDM was a low-toxic compound. In an in vivo antibacterial effect study, NPDM exhibited a better therapeutic effect than tiamulin against MRSA in a mouse thigh infection model as well as a mouse systemic infection model with neutropenia. The 50% effective dose (ED50) of NPDM in a Galleria mellonella infection model was 50.53 mg/kg. The pharmacokinetic properties of NPDM were also measured, which showed that NPDM was a rapid elimination drug in mice.

Sign in / Sign up

Export Citation Format

Share Document