scholarly journals Comparative Genome Sequence Analyses of Geographic Samples of Aspergillus fumigatus—Relevance for Amphotericin B Resistance

2020 ◽  
Vol 8 (11) ◽  
pp. 1673
Author(s):  
Yuying Fan ◽  
Yue Wang ◽  
Jianping Xu
Keyword(s):  
Aspergillus Fumigatus ◽  
Amphotericin B ◽  
Fungal Pathogens ◽  
Molecular Mechanisms ◽  
Fungal Infections ◽  
High Rate ◽  
Whole Genome ◽  
Nucleotide Polymorphisms ◽  
Genome Sequences ◽  
Resistant Strains

Amphotericin B (AMB) is a major fungicidal polyene agent that has a broad spectrum of action against invasive fungal infections. AMB is typically used as the last-line drug against serious and life-threatening infections when other drugs have failed to eliminate the fungal pathogens. Recently, AMB resistance in Aspergillus fumigatus has become more evident. For example, a high rate of AMB resistance (96%) was noted in the A. fumigatus population in Hamilton, Ontario, Canada. AMB-resistant strains have also been found in other countries. However, the mechanism of AMB resistance remains largely unknown. Here, we investigated the potential genes and mutations associated with AMB resistance using whole-genome sequences and examined AMB resistance distribution among genetic populations. A total of 196 whole-genome sequences representing strains from 11 countries were examined. Analyses of single nucleotide polymorphisms (SNPs) at the whole-genome level revealed that these strains belonged to three divergent genetic clusters, with the majority (90%) of AMB resistant strains located in one of the three clusters, Cluster 2. Our analyses identified over 60 SNPs significantly associated with AMB resistance. Together, these SNPs represent promising candidates from which to investigate the putative molecular mechanisms of AMB resistance and for their potential use in developing rapid diagnostic markers for clinical screening of AMB resistance in A. fumigatus.

scholarly journals 1456. Resistance Mechanisms of Tigecycline in Enterococcus faecalis

2020 ◽  
Vol 7 (Supplement_1) ◽  
pp. S730-S731
Author(s):  
Bing Bai ◽  
Zewen Wen ◽  
Zhiwei Lin ◽  
Tam Vincent H ◽  
Zhijian Yu
Keyword(s):  
Enterococcus Faecalis ◽  
Molecular Mechanisms ◽  
Genetic Mutations ◽  
Dilution Method ◽  
Agar Dilution Method ◽  
Whole Genome ◽  
Synonymous Mutations ◽  
Target Sites ◽  
Parental Isolate ◽  
Resistant Strains

Abstract Background Enterococcus faecalis have been regarded as one of the leading causes of the nosocomial infections worldwide. Tigecycline (TGC) is considered as a choice of last resort for the treatment of infections caused by multidrug-resistant E. faecalis, however, the emergence of TGC non-susceptibility has posted the therapeutic challenge. Non-susceptibility in clinical strains could be due to resistance (MIC >0.5 mg/l) or heteroresistance. Therefore, this study aimed to understand the underlying molecular mechanisms of TGC resistance and heteroresistance in E. faecalis. Methods In vitro induction experiments were carried out under TGC pressure with two TGC- sensitive E. faecalis strains. Heteroresistance was evaluated by population analysis profiling (PAP) in 270 clinical TGC- sensitive E. faecalis strains. TGC susceptibility was determined by the agar dilution method. Resistance and heteroresistance mechanisms were investigated by identifying genetic mutations in tetracycline (Tet) target sites and susceptibility testing in the presence of the efflux protein inhibitors phenylalanine-arginine-β-naphthylamide (PaβN) and carbonyl cyanide m chlorophenylhydrazine (CCCP). Comparison of single nucleotide polymorphism in the whole genome between the parental isolate and two TGC-resistant strains were investigated by next-generation sequencing. Results No mutations in Tet target sites in seven TGC heteroresistant strains were present, whereas the mutations in Tet target sites of seven TGC-resistant E. faecalis were frequently found (Table 1). TGC MICs in heteroresistant strains were reduced by CCCP (Table 2). Whole genome sequencing revealed the same non-synonymous mutations and transcoding deletions in the exons of several genes encoding for various enzymes or transfer systems (Table 3). Table 1. The characteristics of the antimicrobial susceptibility, resistance mechanism of TGC-induced resistant isolates Table 2. Characteristics of clinical heteroresistant mother E. faecalis strains and heteroresistance-derived E. faecalis clones Table 3. List of mutation-related genes, amino acids and proteins by comparison of whole genome between the parental isolate and the TGC-induced resistant strains Conclusion Our data indicated that the main mechanism of TGC heteroresistance in E. faecalis might be associated with the efflux pumps. TGC resistance in E. faecalis was associated with mutations in the 16SrRNA site or 30S ribosome protein S10. The genetic mutations in several enzymes and transfer systems might also participate in the resistance development to TGC in E. faecalis. Disclosures All Authors: No reported disclosures

Resistance to antifungal therapies

2017 ◽  
Vol 61 (1) ◽  
pp. 157-166 ◽  
Author(s):  
Rajendra Prasad ◽  
Atanu Banerjee ◽  
Abdul Haseeb Shah
Keyword(s):  
Fungal Pathogens ◽  
Molecular Mechanisms ◽  
Fungal Infections ◽  
Therapeutic Strategies ◽  
Antifungal Resistance ◽  
Antifungal Drugs ◽  
Therapeutic Interventions ◽  
Medical Professionals ◽  
Comprehensive Understanding ◽  
Novel Targets

The evolution of antifungal resistance among fungal pathogens has rendered the limited arsenal of antifungal drugs futile. Considering the recent rise in the number of nosocomial fungal infections in immunocompromised patients, the emerging clinical multidrug resistance (MDR) has become a matter of grave concern for medical professionals. Despite advances in therapeutic interventions, it has not yet been possible to devise convincing strategies to combat antifungal resistance. Comprehensive understanding of the molecular mechanisms of antifungal resistance is essential for identification of novel targets that do not promote or delay emergence of drug resistance. The present study discusses features and limitations of the currently available antifungals, mechanisms of antifungal resistance and highlights the emerging therapeutic strategies that could be deployed to combat MDR.

scholarly journals Widespread amphotericin B-resistant strains of Aspergillus fumigatus in Hamilton, Canada

2018 ◽  
Vol Volume 11 ◽  
pp. 1549-1555 ◽  
Author(s):  
Eta E Ashu ◽  
Gregory A Korfanty ◽  
Himeshi Samarasinghe ◽  
Nicole Pum ◽  
Man You ◽  
...  
Keyword(s):  
Aspergillus Fumigatus ◽  
Amphotericin B ◽  
Resistant Strains

scholarly journals Proteomic and Transcriptomic Analysis of Aspergillus fumigatus on Exposure to Amphotericin B

2008 ◽  
Vol 52 (12) ◽  
pp. 4220-4227 ◽  
Author(s):  
Poonam Gautam ◽  
Jata Shankar ◽  
Taruna Madan ◽  
Ravi Sirdeshmukh ◽  
Curam Sreenivasacharlu Sundaram ◽  
...  
Keyword(s):  
Aspergillus Fumigatus ◽  
Differential Expression ◽  
Amphotericin B ◽  
Stress Proteins ◽  
Fungal Infections ◽  
Antifungal Drug ◽  
Transcriptomic Analysis ◽  
Differentially Expressed ◽  
Specific Response ◽  
Expression Levels

ABSTRACT Amphotericin B (AMB) is the most widely used polyene antifungal drug for the treatment of systemic fungal infections, including invasive aspergillosis. It has been our aim to understand the molecular targets of AMB in Aspergillus fumigatus by genomic and proteomic approaches. In transcriptomic analysis, a total of 295 genes were found to be differentially expressed (165 upregulated and 130 downregulated), including many involving the ergosterol pathway, cell stress proteins, cell wall proteins, transport proteins, and hypothetical proteins. Proteomic profiles of A. fumigatus alone or A. fumigatus treated with AMB showed differential expression levels for 85 proteins (76 upregulated and 9 downregulated). Forty-eight of them were identified with high confidence and belonged to the above-mentioned categories. Differential expression levels for Rho-GDP dissociation inhibitor (Rho-GDI), secretory-pathway GDI, clathrin, Sec 31 (a subunit of the exocyst complex), and RAB GTPase Ypt51 in response to an antifungal drug are reported here for the first time and may represent a specific response of A. fumigatus to AMB. The expression of some of these genes was validated by real-time reverse transcription-PCR. The AMB responsive genes/proteins observed to be differentially expressed in A. fumigatus may be further explored for novel drug development.

scholarly journals Draft Genome Sequences of Two Extensively Drug-Resistant Strains ofMycobacterium tuberculosisBelonging to the Euro-American S Lineage

2016 ◽  
Vol 4 (2) ◽  
Author(s):  
Lesibana A. Malinga ◽  
Thomas Abeel ◽  
Christopher A. Desjardins ◽  
Talent C. Dlamini ◽  
Gail Cassell ◽  
...  
Keyword(s):  
Draft Genome ◽  
Drug Efflux ◽  
Drug Resistant ◽  
Nucleotide Polymorphisms ◽  
Genome Sequences ◽  
Single Nucleotide ◽  
Resistant Tuberculosis ◽  
Extensively Drug Resistant ◽  
Resistant Strains ◽  
Drug Resistant Strains

We report the whole-genome sequencing of two extensively drug-resistant tuberculosis strains belonging to the Euro-American S lineage. The RSA 114 strain showed single-nucleotide polymorphisms predicted to have drug efflux activity.

scholarly journals Antimicrobial resistance among fungi from patients with urinary tract infections in Ojo, Lagos, Nigeria

2021 ◽  
Vol 14 (03) ◽  
pp. 254-264
Author(s):  
Dauphin Dighitoghi Moro ◽  
Oluwole Moses David
Keyword(s):  
Urinary Tract ◽  
Amphotericin B ◽  
Urinary Tract Infections ◽  
Fungal Pathogens ◽  
Fungal Infections ◽  
Antifungal Susceptibility ◽  
Candida Spp ◽  
Fungal Isolates ◽  
Vaginal Swabs ◽  
Tract Infections

The incidence of fungal urinary tract infections has risen gradually and has thus constituted a public health challenge. The aim of this study was to determine the prevalence of urinary tract infections by fungi in two health centres in Ojo, Lagos. A total of 200 patients attending the health centers constituting 160 males’ urines and 40 females’ vaginal swabs were recruited for this study. Midstream urine samples and vaginal swabs were aseptically collected and processed using standard mycological techniques. Fungal isolates were identified based on cultural characteristics, lactophenol blue stain, chlamydospore formation, colony colour on CHROM agar Candida medium and API yeast identification. Antifungal susceptibility testing of the isolates was performed by using the Broth dilution and Kirby-Bauer disk diffusion methods using two of the most commonly used antifungal agents. A total of 122 fungal isolates, of which 68 (55.7%) were Candida spp. and 54(44.3%) Aspergillus spp. were recovered. The Candida spp. included 64 (52.5%) C. albicans and 4(3.3%) C. glabrata while Aspergillus spp. included A. flavus, 20(16.4%), A. fumigatus, 24 (19.8%) and A niger, 10(8.2%). The most common fungal pathogens in the urinary tracts of the subjects were Candida albicans and Aspergillus fumigatus. Both C. albicans and A. fumigatus were highly susceptible to both fluconazole and amphotericin B in dimethyl sulphoxide and water (90-100%). Similarly, all Aspergillus spp. were susceptible to both antifungals except A. flavus which showed a slight resistance (10-15%), which appears to be emerging. Both fluconazole and amphotericin B still show high chances of therapeutic efficacy against fungal infections of the urinary tracts.

scholarly journals Genetic Determinants of Biofilm Formation and Antibiotic Resistance of Helicobacter Pylori using Whole Genome Sequencing

2021 ◽  
Author(s):  
Kartika Afrida Fauzia ◽  
Hafeza Aftab ◽  
Muhammad Miftahussurur ◽  
Langgeng Agung Waskito ◽  
Vo Phuoc Tuan ◽  
...  
Keyword(s):  
Helicobacter Pylori ◽  
Antibiotic Resistance ◽  
Biofilm Formation ◽  
Cross Sectional Study ◽  
Whole Genome ◽  
Nucleotide Polymorphisms ◽  
Genetic Determinants ◽  
Genome Sequences ◽  
Cross Sectional ◽  
H Pylori

Abstract The nucleotide polymorphisms (SNPs) associated with the biofilm formation phenotype of Helicobacter pylori were investigated. Fifty-six H. pylori isolates from Bangladeshi patients were included in this cross-sectional study. Crystal violet was used to classify the phenotypes into high- and low-biofilm formers. Whole genome sequences were analyzed using the “Antimicrobial Resistance Identification By Assembly” (ARIBA) pipeline. The results indicated 19.6% high- and 81.4% low-biofilm formers. These phenotypes were not related to specific clades in the phylogenetic analysis. Biofilm formation was significantly associated with SNPs of alpA, alpB, cagE, cgt, csd4, csd5, futB, gluP, homD, and murF (P < 0.05). Among the SNPs reported in alpB, strains encoding the N156K, G160S, and A223V mutations were high-biofilm formers. Mutations associated with antibiotic resistance can be detected. This study revealed the potential role of SNPs to biofilm formation, and propose a method to detect mutation in antibiotic resistance and biofilm from whole genome sequences.

scholarly journals The Siderophore Transporters Sit1 and Sit2 Are Essential for Utilization of Ferrichrome-, Ferrioxamine- and Coprogen-Type Siderophores in Aspergillus fumigatus

2021 ◽  
Vol 7 (9) ◽  
pp. 768
Author(s):  
Mario Aguiar ◽  
Thomas Orasch ◽  
Matthias Misslinger ◽  
Anna-Maria Dietl ◽  
Fabio Gsaller ◽  
...  
Keyword(s):  
Aspergillus Fumigatus ◽  
Filamentous Fungi ◽  
Fungal Pathogens ◽  
Fungal Infections ◽  
The Novel ◽  
Human Pathogen ◽  
Substrate Specificities ◽  
Triacetylfusarinine C ◽  
Opportunistic Human Pathogen ◽  
Siderophore Transporter

Siderophore-mediated acquisition of iron has been shown to be indispensable for the virulence of several fungal pathogens, the siderophore transporter Sit1 was found to mediate uptake of the novel antifungal drug VL-2397, and siderophores were shown to be useful as biomarkers as well as for imaging of fungal infections. However, siderophore uptake in filamentous fungi is poorly characterized. The opportunistic human pathogen Aspergillus fumigatus possesses five putative siderophore transporters. Here, we demonstrate that the siderophore transporters Sit1 and Sit2 have overlapping, as well as unique, substrate specificities. With respect to ferrichrome-type siderophores, the utilization of ferrirhodin and ferrirubin depended exclusively on Sit2, use of ferrichrome A depended mainly on Sit1, and utilization of ferrichrome, ferricrocin, and ferrichrysin was mediated by both transporters. Moreover, both Sit1 and Sit2 mediated use of the coprogen-type siderophores coprogen and coprogen B, while only Sit1 transported the bacterial ferrioxamine-type xenosiderophores ferrioxamines B, G, and E. Neither Sit1 nor Sit2 were important for the utilization of the endogenous siderophores fusarinine C and triacetylfusarinine C. Furthermore, A. fumigatus was found to lack utilization of the xenosiderophores schizokinen, basidiochrome, rhizoferrin, ornibactin, rhodotorulic acid, and enterobactin. Taken together, this study characterized siderophore use by A. fumigatus and substrate characteristics of Sit1 and Sit2.

scholarly journals Fun(gi)omics: Advanced and Diverse Technologies to Explore Emerging Fungal Pathogens and Define Mechanisms of Antifungal Resistance

mBio ◽  
2020 ◽  
Vol 11 (5) ◽  
Author(s):  
B. Ball ◽  
M. Langille ◽  
J. Geddes-McAlister
Keyword(s):  
Fungal Pathogens ◽  
Fungal Infections ◽  
Emerging Pathogens ◽  
Current State ◽  
Geographical Regions ◽  
Fungal Adaptation ◽  
Resistant Strains ◽  
Integration Strategies ◽  
And Control ◽  
Emerging Fungal Pathogens

ABSTRACT The landscape of infectious fungal agents includes previously unidentified or rare pathogens with the potential to cause unprecedented casualties in biodiversity, food security, and human health. The influences of human activity, including the crisis of climate change, along with globalized transport, are underlying factors shaping fungal adaptation to increased temperature and expanded geographical regions. Furthermore, the emergence of novel antifungal-resistant strains linked to excessive use of antifungals (in the clinic) and fungicides (in the field) offers an additional challenge to protect major crop staples and control dangerous fungal outbreaks. Hence, the alarming frequency of fungal infections in medical and agricultural settings requires effective research to understand the virulent nature of fungal pathogens and improve the outcome of infection in susceptible hosts. Mycology-driven research has benefited from a contemporary and unified approach of omics technology, deepening the biological, biochemical, and biophysical understanding of these emerging fungal pathogens. Here, we review the current state-of-the-art multi-omics technologies, explore the power of data integration strategies, and highlight discovery-based revelations of globally important and taxonomically diverse fungal pathogens. This information provides new insight for emerging pathogens through an in-depth understanding of well-characterized fungi and provides alternative therapeutic strategies defined through novel findings of virulence, adaptation, and resistance.

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