scholarly journals The first multi-omic interaction network in the human pathogen Candida glabrata provides novel insights into the virulence regulator, Hsp90

2021 ◽  
Vol 3 (12) ◽  
Author(s):  
Julia Crunden ◽  
Ken Haynes ◽  
Stephanie Diezmann
Keyword(s):  
Drug Resistance ◽  
Candida Glabrata ◽  
Drug Targets ◽  
Interaction Network ◽  
Heat Shock Protein 90 ◽  
Genetic Network ◽  
Resistance Mechanisms ◽  
Hsp90 Inhibitor ◽  
Antibiotic Biosynthesis ◽  
Close Relatives

Candida glabrata-caused candidiasis is growing but treatments remain limited by paucity of drug targets, intrinsic azole resistance and increasing resistance to other drug classes. Drug resistance is one of numerous virulence traits regulated by the chaperone, heat shock protein 90 (Hsp90) in Candida albicans via its interactions with 5% of the genome. Hsp90 also regulates key drug resistance mechanisms in C. glabrata, but little else was known about Hsp90 in this organism. Therefore, CgHsp90 interactions were elucidated by genetic and proteomic methods. A genetic network was produced by a chemical-genetic, synthetic-sick screen on a gene-deletion library covering 16% of the genome; whilst quantitative proteomics was undertaken by tandem mass tagging on wild-type cells. Both experiments were undertaken at 30°C, 37°C and 39°C and Hsp90 was perturbed using sub-lethal concentrations of Hsp90 inhibitor. Efforts to identify Hsp90 interactors at these host-infection associated temperatures produced a genetic network of 68 genes and a protein network of 2298 proteins. Of these, 4 genes and 261 proteins interacted with Hsp90 at all three temperatures, indicating a core Hsp90 interaction network. Intriguingly, both networks had enrichment for the “antibiotic biosynthesis” GO term. Two genes, BCY1 and MCM16, were found to interact with Hsp90 at multiple temperatures in both networks. These data indicate the divergence of Hsp90 networks between C. glabrata and its close relatives and offer important targets for further research. Presented here is the first multi-omic interaction network in C. glabrata, focused on the virulence and drug resistance regulator, Hsp90.

scholarly journals Mapping the malaria parasite drug-able genome using in vitro evolution and chemogenomics

2017 ◽  
Author(s):  
Annie N. Cowell ◽  
Eva S. Istvan ◽  
Amanda K. Lukens ◽  
Maria G. Gomez-Lorenzo ◽  
Manu Vanaerschot ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Plasmodium Falciparum ◽  
Multidrug Resistance ◽  
Resistance Genes ◽  
Genome Analysis ◽  
Drug Targets ◽  
Malaria Parasite ◽  
Resistance Mechanisms ◽  
Whole Genome

AbstractChemogenetic characterization through in vitro evolution combined with whole genome analysis is a powerful tool to discover novel antimalarial drug targets and identify drug resistance genes. Our comprehensive genome analysis of 262 Plasmodium falciparum parasites treated with 37 diverse compounds reveals how the parasite evolves to evade the action of small molecule growth inhibitors. This detailed data set revealed 159 gene amplifications and 148 nonsynonymous changes in 83 genes which developed during resistance acquisition. Using a new algorithm, we show that gene amplifications contribute to 1/3 of drug resistance acquisition events. In addition to confirming known multidrug resistance mechanisms, we discovered novel multidrug resistance genes. Furthermore, we identified promising new drug target-inhibitor pairs to advance the malaria elimination campaign, including: thymidylate synthase and a benzoquinazolinone, farnesyltransferase and a pyrimidinedione, and a dipeptidylpeptidase and an arylurea. This deep exploration of the P. falciparum resistome and drug-able genome will guide future drug discovery and structural biology efforts, while also advancing our understanding of resistance mechanisms of the deadliest malaria parasite.One Sentence SummaryWhole genome sequencing reveals how Plasmodium falciparum evolves resistance to diverse compounds and identifies new antimalarial drug targets.

scholarly journals High-throughput decoding of drug targets and drug resistance mechanisms in African trypanosomes

Parasitology ◽  
2013 ◽  
Vol 141 (1) ◽  
pp. 77-82 ◽  
Author(s):  
DAVID HORN
Keyword(s):  
Drug Resistance ◽  
High Throughput ◽  
Drug Targets ◽  
Sequence Data ◽  
Resistance Mechanisms ◽  
New Drugs ◽  
Drug Uptake ◽  
Microbial Pathogens ◽  
African Trypanosomes ◽  
Genome Scale

SUMMARYThe availability of genome sequence data has facilitated the development of high-throughput genetic screening approaches in microbial pathogens. In the African trypanosome, Trypanosoma brucei, genome-scale RNA interference screens have proven particularly effective in this regard. These genetic screens allow for identification of the genes that contribute to a particular pathway or mechanisms of interest. The approach has been used to assess loss-of-fitness, revealing the genes and proteins required for parasite viability and growth. The outputs from these screens predict essential and dispensable genes and facilitate drug target prioritization efforts. The approach has also been used to assess resistance to anti-trypanosomal drugs, revealing the genes and proteins that facilitate drug uptake and action. These outputs also highlight likely mechanisms underlying clinically relevant drug resistance. I first review these findings in the context of what we know about current drugs. I then describe potential contributions that these high-throughput approaches could make to the development and implementation of new drugs.

scholarly journals Gambogic acid identifies an isoform-specific druggable pocket in the middle domain of Hsp90β

2016 ◽  
Vol 113 (33) ◽  
pp. E4801-E4809 ◽  
Author(s):  
Kendrick H. Yim ◽  
Thomas L. Prince ◽  
Shiwei Qu ◽  
Fang Bai ◽  
Patricia A. Jennings ◽  
...  
Keyword(s):  
Molecular Chaperone ◽  
Drug Targets ◽  
Heat Shock Protein 90 ◽  
Hsp90 Inhibitor ◽  
Gambogic Acid ◽  
Disease States ◽  
Middle Domain ◽  
Health And Disease ◽  
A Site

Because of their importance in maintaining protein homeostasis, molecular chaperones, including heat-shock protein 90 (Hsp90), represent attractive drug targets. Although a number of Hsp90 inhibitors are in preclinical/clinical development, none strongly differentiate between constitutively expressed Hsp90β and stress-induced Hsp90α, the two cytosolic paralogs of this molecular chaperone. Thus, the importance of inhibiting one or the other paralog in different disease states remains unknown. We show that the natural product, gambogic acid (GBA), binds selectively to a site in the middle domain of Hsp90β, identifying GBA as an Hsp90β-specific Hsp90 inhibitor. Furthermore, using computational and medicinal chemistry, we identified a GBA analog, referred to as DAP-19, which binds potently and selectively to Hsp90β. Because of its unprecedented selectivity for Hsp90β among all Hsp90 paralogs, GBA thus provides a new chemical tool to study the unique biological role of this abundantly expressed molecular chaperone in health and disease.

Drug resistance mechanisms and novel drug targets for tuberculosis therapy

2017 ◽  
Vol 44 (1) ◽  
pp. 21-37 ◽  
Author(s):  
Md Mahmudul Islam ◽  
H.M. Adnan Hameed ◽  
Julius Mugweru ◽  
Chiranjibi Chhotaray ◽  
Changwei Wang ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Drug Targets ◽  
Resistance Mechanisms ◽  
Tuberculosis Therapy ◽  
Novel Drug ◽  
Novel Drug Targets

scholarly journals Intracellular Drug Targets In Mycobacterium Tuberculosis Revealed By A Chemo-Genetic Approach

2021 ◽  
Author(s):  
Clement K.M. Tsui ◽  
Flavia Sorrentino ◽  
Narula Gagandeep ◽  
Alfonso Mendoza Losanna ◽  
Ruben Gonzalez Rio ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Mycobacterium Tuberculosis ◽  
Drug Targets ◽  
Resistance Mechanisms ◽  
Sequencing Analysis ◽  
Chronic Lung Diseases ◽  
Candidate Drug ◽  
A Genome ◽  
Novel Drug

Abstract Mycobacterium tuberculosis (Mtb), the etiological agent of tuberculosis, is one of the most devastating infectious agents in the world. It causes chronic lung diseases to one third of the world’s population. Chemo-genetic characterization through in vitro evolution combined with whole genome sequencing analysis can identify novel drug targets and drug resistance genes in Mtb. We performed a genome analysis of 53 Mtb mutants resistant to 15 different hit compounds. We found nonsynonymous mutations/indels in 30 genes that may be associated with drug resistance acquisitions. Beyond confirming previously identified drug resistance mechanisms such as rpoB and lead targets reported in novel anti-tuberculosis drug screenings such as mmpL3, ethA, mbtA, we discovered several unrecognized candidate drug targets including prrB and TB18.5. The exploration of the M. tuberculosis chemical mutant genomes could help novel drug discovery and structural biology of compounds and asscoiated mechanisms of action relevant to tuberculosis treatment.

scholarly journals Mapping the malaria parasite druggable genome by using in vitro evolution and chemogenomics

Science ◽  
2018 ◽  
Vol 359 (6372) ◽  
pp. 191-199 ◽  
Author(s):  
Annie N. Cowell ◽  
Eva S. Istvan ◽  
Amanda K. Lukens ◽  
Maria G. Gomez-Lorenzo ◽  
Manu Vanaerschot ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Genome Analysis ◽  
Drug Targets ◽  
Malaria Parasite ◽  
Resistance Mechanisms ◽  
Whole Genome Analysis ◽  
In Vitro Evolution ◽  
A Genome ◽  
Druggable Genome

Chemogenetic characterization through in vitro evolution combined with whole-genome analysis can identify antimalarial drug targets and drug-resistance genes. We performed a genome analysis of 262 Plasmodium falciparum parasites resistant to 37 diverse compounds. We found 159 gene amplifications and 148 nonsynonymous changes in 83 genes associated with drug-resistance acquisition, where gene amplifications contributed to one-third of resistance acquisition events. Beyond confirming previously identified multidrug-resistance mechanisms, we discovered hitherto unrecognized drug target–inhibitor pairs, including thymidylate synthase and a benzoquinazolinone, farnesyltransferase and a pyrimidinedione, and a dipeptidylpeptidase and an arylurea. This exploration of the P. falciparum resistome and druggable genome will likely guide drug discovery and structural biology efforts, while also advancing our understanding of resistance mechanisms available to the malaria parasite.

Fatty Acid Biosynthesis: an updated review on KAS inhibitors

2022 ◽  
Vol 19 ◽  
Author(s):  
Rani Shinde ◽  
Vasanti Suvarna
Keyword(s):  
Drug Resistance ◽  
Fatty Acid ◽  
Drug Targets ◽  
Fatty Acid Biosynthesis ◽  
Resistance Mechanisms ◽  
Acid Biosynthesis ◽  
E Coli ◽  
Metabolic Mechanism ◽  
Modern Era ◽  
Early Drug

Abstract: Since the early twentieth century, with the isolation of penicillin and streptomycin in the 1940s, the modern era of anti-infective drug development has gained momentum. Due to the enormous success of early drug discovery, many infectious diseases were successfully prevented & eradicated. However, this initial hope was wrongheaded, and pathogens evolved as a significant threat to human health. Drug resistance develops as a result of natural selection's relentless pressure, necessitating the identification of new drug targets and the creation of chemotherapeutics that bypass existing drug resistance mechanisms. Fatty acid biosynthesis (FAS) is a crucial metabolic mechanism for bacteria during their growth and development. Several crucial enzymes involved in this biosynthetic pathway have been identified as potential targets for new antibacterial agents. In Escherichia coli (E. coli), this pathway has been extensively investigated. The present review focuses on progress in the development of Kas A, Kas B, and Fab H inhibitors as mono-therapeutic antibiotics.

Genetic and Epigenetic Modulation of Drug Resistance in Cancer: Challenges and Opportunities

2020 ◽  
Vol 20 (14) ◽  
pp. 1114-1131 ◽  
Author(s):  
Kanisha Shah ◽  
Rakesh M. Rawal
Keyword(s):  
Drug Resistance ◽  
Drug Targets ◽  
Complex Disease ◽  
Cancer Therapies ◽  
Altered Expression ◽  
Acquired Drug Resistance ◽  
Challenges And Opportunities ◽  
Chemotherapeutic Treatment ◽  
Epigenetic Modulation ◽  
Targeted Drug Therapies

Cancer is a complex disease that has the ability to develop resistance to traditional therapies. The current chemotherapeutic treatment has become increasingly sophisticated, yet it is not 100% effective against disseminated tumours. Anticancer drugs resistance is an intricate process that ascends from modifications in the drug targets suggesting the need for better targeted therapies in the therapeutic arsenal. Advances in the modern techniques such as DNA microarray, proteomics along with the development of newer targeted drug therapies might provide better strategies to overcome drug resistance. This drug resistance in tumours can be attributed to an individual’s genetic differences, especially in tumoral somatic cells but acquired drug resistance is due to different mechanisms, such as cell death inhibition (apoptosis suppression) altered expression of drug transporters, alteration in drug metabolism epigenetic and drug targets, enhancing DNA repair and gene amplification. This review also focusses on the epigenetic modifications and microRNAs, which induce drug resistance and contributes to the formation of tumour progenitor cells that are not destroyed by conventional cancer therapies. Lastly, this review highlights different means to prevent the formation of drug resistant tumours and provides future directions for better treatment of these resistant tumours.

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