scholarly journals Drosophila melanogasteras a Facile Model for Large‐Scale Studies of Virulence Mechanisms and Antifungal Drug Efficacy inCandidaSpecies

2006 ◽  
Vol 193 (7) ◽  
pp. 1014-1022 ◽  
Author(s):  
Georgios Chamilos ◽  
Michail S. Lionakis ◽  
Russell E. Lewis ◽  
Jose L. Lopez‐Ribot ◽  
Stephen P. Saville ◽  
...  
Keyword(s):  
Large Scale ◽  
Drug Efficacy ◽  
Antifungal Drug

scholarly journals 380. Drosophila melanogaster as a Facile Model for Large-Scale Studies of Virulence Mechanisms and Antifungal Drug Efficacy in Candida auris Candidiasis

2018 ◽  
Vol 5 (suppl_1) ◽  
pp. S147-S148
Author(s):  
Ashwini Bandi ◽  
Sebastian Wurster ◽  
Nitya M Raman ◽  
Nathaniel Albert ◽  
Issam I Raad ◽  
...  
Keyword(s):  
Drosophila Melanogaster ◽  
Large Scale ◽  
Drug Efficacy ◽  
Antifungal Drug ◽  
Candida Auris

scholarly journals Integrative pharmacogenomics to infer large-scale drug taxonomy

2016 ◽  
Author(s):  
Nehme El-Hachem ◽  
Deena M.A. Gendoo ◽  
Laleh Soltan Ghoraie ◽  
Zhaleh Safikhani ◽  
Petr Smirnov ◽  
...  
Keyword(s):  
Drug Targets ◽  
Large Scale ◽  
Prior Information ◽  
Structural Information ◽  
Drug Efficacy ◽  
Basic Drug ◽  
Flexible Tool ◽  
Experimental Drugs ◽  
New Compounds ◽  
Novel Drug

ABSTRACTIdentification of drug targets and mechanism of action (MoA) for new and uncharacterlzed drugs is important for optimization of drug efficacy. Current MoA prediction approaches largely rely on prior information including side effects, therapeutic indication and/or chemo-informatics. Such information is not transferable or applicable for newly identified, previously uncharacterlzed small molecules. Therefore, a shift in the paradigm of MoA predictions is necessary towards development of unbiased approaches that can elucidate drug relationships and efficiently classify new compounds with basic input data. We propose a new integrative computational pharmacogenomlc approach, referred to as Drug Network Fusion (DNF), to infer scalable drug taxonomies that relies only on basic drug characteristics towards elucidating drug-drug relationships. DNF is the first framework to integrate drug structural information, high-throughput drug perturbation and drug sensitivity profiles, enabling drug classification of new experimental compounds with minimal prior information. We demonstrate that the DNF taxonomy succeeds in identifying pertinent and novel drug-drug relationships, making it suitable for investigating experimental drugs with potential new targets or MoA. We highlight how the scalability of DNF facilitates identification of key drug relationships across different drug categories, and poses as a flexible tool for potential clinical applications in precision medicine. Our results support DNF as a valuable resource to the cancer research community by providing new hypotheses on the compound MoA and potential insights for drug repurposlng.

Tumoral Drug Metabolism: Overview and Its Implications for Cancer Therapy

2005 ◽  
Vol 23 (1) ◽  
pp. 205-229 ◽  
Author(s):  
M. Michael ◽  
M.M. Doherty
Keyword(s):  
Cancer Therapy ◽  
Drug Metabolism ◽  
Large Scale ◽  
New Technologies ◽  
Drug Efficacy ◽  
Metabolizing Enzymes ◽  
Therapeutic Implications ◽  
Firm Data ◽  
The Individual

Drug-metabolizing enzymes (DME) in tumors are capable of biotransforming a variety of xenobiotics, including antineoplastics, resulting in either their activation or detoxification. Many studies have reported the presence of DME in tumors; however, heterogenous detection methodology and patient cohorts have not generated consistent, firm data. Nevertheless, various gene therapy approaches and oral prodrugs have been devised, taking advantage of tumoral DME. With the need to target and individualize anticancer therapies, tumoral processes such as drug metabolism must be considered as both a potential mechanism of resistance to therapy and a potential means of achieving optimal therapy. This review discusses cytotoxic drug metabolism by tumors, through addressing the classes of the individual DME, their relevant substrates, and their distribution in specific malignancies. The limitations of preclinical models relative to the clinical setting and lack of data on the changes of DME with disease progression and host response will be discussed. The therapeutic implications of tumoral drug metabolism will be addressed—in particular, the role of DME in predicting therapeutic response, the activation of prodrugs, and the potential for modulation of their activity for gain are considered, with relevant clinical examples. The contribution of tumoral drug metabolism to cancer therapy can only be truly ascertained through large-scale prospective studies and supported by new technologies for tumor sampling and genetic analysis such as microarrays. Only then can efforts be concentrated in the design of better prodrugs or combination therapy to improve drug efficacy and individualize therapy.

scholarly journals A vascularized and perfused organ-on-a-chip platform for large-scale drug screening applications

Lab on a Chip ◽  
2017 ◽  
Vol 17 (3) ◽  
pp. 511-520 ◽  
Author(s):  
Duc T. T. Phan ◽  
Xiaolin Wang ◽  
Brianna M. Craver ◽  
Agua Sobrino ◽  
Da Zhao ◽  
...  
Keyword(s):  
Drug Screening ◽  
Large Scale ◽  
Drug Efficacy ◽  
Toxicity Screening ◽  
Organ On A Chip

A vascularized, perfused organ-on-a-chip platform suitable for large-scale drug efficacy/toxicity screening.

scholarly journals Toll‐DeficientDrosophilaFlies as a Fast, High‐Throughput Model for the Study of Antifungal Drug Efficacy against Invasive Aspergillosis andAspergillusVirulence

2005 ◽  
Vol 191 (7) ◽  
pp. 1188-1195 ◽  
Author(s):  
Michail S. Lionakis ◽  
Russell E. Lewis ◽  
Gregory S. May ◽  
Nathan P. Wiederhold ◽  
Nathaniel D. Albert ◽  
...  
Keyword(s):  
Invasive Aspergillosis ◽  
High Throughput ◽  
Drug Efficacy ◽  
Antifungal Drug ◽  
Throughput Model

Large-Scale Prediction of Beneficial Drug Combinations Using Drug Efficacy and Target Profiles

2015 ◽  
Vol 55 (12) ◽  
pp. 2705-2716 ◽  
Author(s):  
Hiroaki Iwata ◽  
Ryusuke Sawada ◽  
Sayaka Mizutani ◽  
Masaaki Kotera ◽  
Yoshihiro Yamanishi
Keyword(s):  
Large Scale ◽  
Drug Efficacy ◽  
Drug Combinations

scholarly journals A novel CRISPRi platform to study the role of essential genes in antifungal drug-resistant Candida albicans isolates

2021 ◽  
Vol 3 (12) ◽  
Author(s):  
Lauren Wensing ◽  
Rebecca Shapiro ◽  
Deeva Uthayakumar ◽  
Viola Halder ◽  
Jehoshua Sharma ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Transcriptional Repression ◽  
Drug Targets ◽  
Large Scale ◽  
Essential Gene ◽  
Essential Genes ◽  
Antifungal Drugs ◽  
Antifungal Drug ◽  
Drug Resistant ◽  
Fungal Organisms

With the emergence of antifungal resistant Candida albicans strains, the need for new antifungal drugs is critical in combating this fungal pathogen. Investigating essential genes in C. albicans is a vital step in characterizing putative antifungal drug targets. As some of these essential genes are conserved between fungal organisms, developed therapies targeting these genes have the potential to be broad range antifungals. In order to study these essential genes, classical genetic knockout or CRISPR-based approaches cannot be used as disrupting essential genes leads to lethality in the organism. Fortunately, a variation of the CRISPR system (CRISPR interference or CRISPRi) exists that enables precise transcriptional repression of the gene of interest without introducing genetic mutations. CRISPRi utilizes an endonuclease dead Cas9 protein that can be targeted to a precise location but lacks the ability to create a double-stranded break. The binding of the dCas9 protein to DNA prevents the binding of RNA polymerase to the promoter through steric hindrance thereby reducing expression. We recently published the novel use of this technology in C. albicans and are currently working on expanding this technology to large scale repression of essential genes. Through the construction of an essential gene CRISPRi-sgRNA library, we can begin to study the function of essential genes under different conditions and identify genes that are involved in critical processes such as drug tolerance in antifungal resistant background strains. These genes can ultimately be characterized as putative targets for novel antifungal drug development, or targeted as a means to sensitize drug-resistant strains to antifungal treatment.

scholarly journals Aiming for a bull’s-eye: Targeting antifungals to fungi with dectin-decorated liposomes

2021 ◽  
Vol 17 (7) ◽  
pp. e1009699
Author(s):  
Richard B. Meagher ◽  
Zachary A. Lewis ◽  
Suresh Ambati ◽  
Xiaorong Lin
Keyword(s):  
Organ Transplant ◽  
Drug Efficacy ◽  
The United States ◽  
Antifungal Drugs ◽  
Fungal Diseases ◽  
Antifungal Drug ◽  
Fungal Cell ◽  
Liposomal Drug ◽  
Invasive Fungal Diseases

Globally, there are several million individuals with life-threatening invasive fungal diseases such as candidiasis, aspergillosis, cryptococcosis, Pneumocystis pneumonia (PCP), and mucormycosis. The mortality rate for these diseases generally exceeds 40%. Annual medical costs to treat these invasive fungal diseases in the United States exceed several billion dollars. In addition to AIDS patients, the risks of invasive mycoses are increasingly found in immune-impaired individuals or in immunosuppressed patients following stem cell or organ transplant or implantation of medical devices. Current antifungal drug therapies are not meeting the challenge, because (1) at safe doses, they do not provide sufficient fungal clearance to prevent reemergence of infection; (2) most become toxic with extended use; (3) drug-resistant fungal isolates are emerging; and (4) only one new class of antifungal drugs has been approved for clinical use in the last 2 decades. DectiSomes represent a novel design of drug delivery to drastically increase drug efficacy. Antifungals packaged in liposomes are targeted specifically to where the pathogen is, through binding to the fungal cell walls or exopolysaccharide matrices using the carbohydrate recognition domains of pathogen receptors. Relative to untargeted liposomal drug, DectiSomes show order of magnitude increases in the binding to and killing of Candida albicans, Cryptococcus neoformans, and Aspergillus fumigatus in vitro and similarly improved efficacy in mouse models of pulmonary aspergillosis. DectiSomes have the potential to usher in a new antifungal drug treatment paradigm.

scholarly journals CRISPR-Based Genetic Manipulation of Candida Species: Historical Perspectives and Current Approaches

2021 ◽  
Vol 2 ◽  
Author(s):  
Deeva Uthayakumar ◽  
Jehoshua Sharma ◽  
Lauren Wensing ◽  
Rebecca S. Shapiro
Keyword(s):  
Large Scale ◽  
Gene Editing ◽  
Genetic Manipulation ◽  
Single Point ◽  
Antifungal Drug ◽  
Sexual Cycle ◽  
Single Point Mutation ◽  
Functional Genomic ◽  
Historical Perspectives ◽  
Genomic Studies

The Candida genus encompasses a diverse group of ascomycete fungi that have captured the attention of the scientific community, due to both their role in pathogenesis and emerging applications in biotechnology; the development of gene editing tools such as CRISPR, to analyze fungal genetics and perform functional genomic studies in these organisms, is essential to fully understand and exploit this genus, to further advance antifungal drug discovery and industrial value. However, genetic manipulation of Candida species has been met with several distinctive barriers to progress, such as unconventional codon usage in some species, as well as the absence of a complete sexual cycle in its diploid members. Despite these challenges, the last few decades have witnessed an expansion of the Candida genetic toolbox, allowing for diverse genome editing applications that range from introducing a single point mutation to generating large-scale mutant libraries for functional genomic studies. Clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 technology is among the most recent of these advancements, bringing unparalleled versatility and precision to genetic manipulation of Candida species. Since its initial applications in Candida albicans, CRISPR-Cas9 platforms are rapidly evolving to permit efficient gene editing in other members of the genus. The technology has proven useful in elucidating the pathogenesis and host-pathogen interactions of medically relevant Candida species, and has led to novel insights on antifungal drug susceptibility and resistance, as well as innovative treatment strategies. CRISPR-Cas9 tools have also been exploited to uncover potential applications of Candida species in industrial contexts. This review is intended to provide a historical overview of genetic approaches used to study the Candida genus and to discuss the state of the art of CRISPR-based genetic manipulation of Candida species, highlighting its contributions to deciphering the biology of this genus, as well as providing perspectives for the future of Candida genetics.

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