scholarly journals Cross kingdom analysis of putative quadruplex-forming sequences in fungal genomes: novel antifungal targets to ameliorate fungal pathogenicity?

2020 ◽  
Author(s):  
Emily F. Warner ◽  
Natália Bohálová ◽  
Václav Brázda ◽  
Zoë A. E. Waller ◽  
Stefan Bidula
Keyword(s):  
Drug Resistance ◽  
Drug Targets ◽  
Protein Modification ◽  
Pathogenic Fungi ◽  
Significant Heterogeneity ◽  
Nucleic Acid Binding ◽  
Fungal Virulence ◽  
Coding Regions ◽  
Critical Requirement ◽  
Novel Drug

AbstractFungi contribute to upwards of 1.5 million human deaths annually, are involved in the spoilage of up to a third of food crops, and have a devastating effect on plant and animal biodiversity. Moreover, this already significant issue is exacerbated by a rise in antifungal resistance and a critical requirement for novel drug targets. Quadruplexes are four-stranded secondary structures in nucleic acids which can regulate processes such as transcription, translation, replication, and recombination. They are also found in genes linked to virulence in microbes, and quadruplex-binding ligands have been demonstrated to eliminate drug resistant pathogens. Using a computational approach, we identified putative quadruplex-forming sequences (PQS) in 1362 genomes across the fungal kingdom and explored their potential involvement in virulence, drug resistance, and pathogenicity. Here we present the largest analysis of PQS in fungi and identified significant heterogeneity of these sequences throughout phyla, genera, and species. Moreover, PQS were genetically conserved. Notably, loss of PQS in cryptococci and aspergilli was associated with pathogenicity. PQS in the clinically important pathogens Aspergillus fumigatus, Cryptococcus neoformans, and Candida albicans were located within genes (particularly coding regions), mRNA, repeat regions, mobile elements, tRNA, ncRNA, rRNA, and the centromere. Genes containing PQS in these organisms were found to be primarily associated with metabolism, nucleic acid binding, transporter activity, and protein modification. Finally, PQS were found in over 100 genes associated with virulence, drug resistance, or key biological processes in these pathogenic fungi and were found in genes which were highly upregulated during germination, hypoxia, oxidative stress, iron limitation, and in biofilms. Taken together, quadruplexes in fungi could present interesting novel targets to ameliorate fungal virulence and overcome drug resistance.

scholarly journals A recent development of new therapeutic agents and novel drug targets for cancer treatment

2021 ◽  
Vol 9 ◽  
pp. 205031212110670
Author(s):  
Zemene Demelash Kifle ◽  
Meklit Tadele ◽  
Eyerusalem Alemu ◽  
Tadele Gedamu ◽  
Akeberegn Gorems Ayele
Keyword(s):  
Drug Resistance ◽  
Cancer Treatment ◽  
Drug Targets ◽  
Therapeutic Agents ◽  
Chemotherapeutic Agents ◽  
Cross Resistance ◽  
Drug Induced ◽  
Induced Apoptosis ◽  
Novel Drug ◽  
Novel Drug Targets

Despite recent advances in cancer diagnosis, prevention, detection, as well as management, the disease is expected to be the top cause of death globally. The chemotherapy approach for cancer has become more advanced in its design, yet no medication can cure enough against all types of cancer and its stage. Thus, this review aimed to summarize a recent development of new therapeutic agents and novel drug targets for the treatment of cancer. Several obstacles stand in the way of effective cancer treatment and drug development, including inaccessibility of tumor site by appropriate drug concentration, debilitating untoward effects caused by non-selective tissue distribution of chemotherapeutic agents, and occurrence of drug resistance, which leads to cross-resistance to a variety of drugs. Resistance to treatment with anticancer drugs results from multiple factors and the most common reason for acquiring drug resistance is marking and expelling drugs that prevent cancer cells to be targeted by chemotherapeutic agents. Moreover, insensitivity to drug-induced apoptosis, alteration, and mutation of drug target and interference/change of DNA replication are other main causes of treatment failure.

scholarly journals Bioorganometallic Compounds as Novel Drug Targets against Schistosomiasis in Sub-Saharan Africa: An alternative to Praziquantel?

2021 ◽  
Author(s):  
Cuma Cumisa Ndamse ◽  
Priscilla Masamba ◽  
Abidemi Paul Kappo
Keyword(s):  
Drug Resistance ◽  
Drug Targets ◽  
Redox Homeostasis ◽  
Organometallic Compounds ◽  
Sub Saharan Africa ◽  
Redox Biology ◽  
Anti Cancer ◽  
Sub Saharan ◽  
Novel Drug ◽  
Novel Drug Targets

Human schistosomiasis is a disease that mostly plagues the destitute of various tropical and sub-tropical countries, particularly in sub-Saharan Africa and South America. It has significant effects on various health and economic-related matters. Globally, the burden of schistosomiasis has been controlled with a single chemotherapeutic drug, Praziquantel, which has recently demonstrated several clinical issues, including its inability to destroy juvenile schistosome worms and drug resistance because of its extensive use. The use of organometallic moieties in biological and medicinal chemistry has developed greatly and has led to their use in various anti-cancer and anti-infectious agents. The abundance of a range of organometallic compounds that can cause damage to the parasite has received tremendous feedback, with many already at clinical trials. The distinct redox biology of the schistosome parasite is a vulnerable element to the survival of the worm and has steered attempts toward the use of redox-directed bioorganometallic compounds. Disruption of the schistosome redox homeostasis through organometallic ions provides a novel drug target that could be used in overcoming the drawbacks of the mainstream drug and one that could possibly bypass the emergence of drug resistance.

A Comparative Review on Current and Future Drug Targets Against Bacteria & Malaria

2020 ◽  
Vol 21 (8) ◽  
pp. 736-775
Author(s):  
Usha K. Rout ◽  
A.S. Sanket ◽  
Brijesh S. Sisodia ◽  
Pradyumna K. Mohapatra ◽  
Sanghamitra Pati ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Infectious Diseases ◽  
Drug Targets ◽  
Pathogenic Bacteria ◽  
Treatment Options ◽  
Treatment Scenario ◽  
Comparative Review ◽  
Future Drug ◽  
Life Threatening ◽  
Novel Drug

Long before the discovery of drugs like ‘antibiotic and anti-parasitic drugs’, the infectious diseases caused by pathogenic bacteria and parasites remain as one of the major causes of morbidity and mortality in developing and underdeveloped countries. The phenomenon by which the organism exerts resistance against two or more structurally unrelated drugs is called multidrug resistance (MDR) and its emergence has further complicated the treatment scenario of infectious diseases. Resistance towards the available set of treatment options and poor pipeline of novel drug development puts an alarming situation. A universal goal in the post-genomic era is to identify novel targets/drugs for various life-threatening diseases caused by such pathogens. This review is conceptualized in the backdrop of drug resistance in two major pathogens i.e. “Pseudomonas aeruginosa” and “Plasmodium falciparum”. In this review, the available targets and key mechanisms of resistance of these pathogens have been discussed in detail. An attempt has also been made to analyze the common drug targets of bacteria and malaria parasite to overcome the current drug resistance scenario. The solution is also hypothesized in terms of a present pipeline of drugs and efforts made by scientific community.

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 A novel Hsp90 phospho-switch modulates virulence in the major human fungal pathogen Candida albicans

2020 ◽  
Author(s):  
Leenah Alaalm ◽  
Julia L. Crunden ◽  
Mark Butcher ◽  
Ulrike Obst ◽  
Ryann Whealy ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Stress Responses ◽  
Fungal Pathogen ◽  
Drug Targets ◽  
Fungal Infections ◽  
Pathogenic Fungi ◽  
First Record ◽  
Drug Susceptibility ◽  
Phosphorylation Sites ◽  
Fungal Virulence

The ubiquitous molecular chaperone Hsp90 is a key regulator of cellular proteostasis and environmental stress responses. Hsp90 also regulates cellular morphogenesis, drug resistance, and virulence in human pathogenic fungi, which kill more than 1.6 million patients each year worldwide. Invasive fungal infections are difficult to treat due to the lack of effective antifungal therapies, resulting in mortality rates of up to 95%. As a key regulator of fungal virulence, Hsp90 is an attractive therapeutic target. However, fungal and animal homologs are highly conserved, impeding fungal-specific targeting. Thus, understanding the factors that regulate Hsp90 could provide an alternative strategy aimed at exclusively targeting this regulator of fungal virulence. Here, we demonstrate how CK2-mediated phosphorylation of two Hsp90 residues modulates virulence in a major fungal pathogen of humans, Candida albicans. We combined proteomics, molecular evolution and structural modelling with molecular biology to identify and characterize two Hsp90 phosphorylation sites. Phosphorylation negatively affects thermal stress response, morphogenesis, drug susceptibility and fungal virulence. Our results provide the first record of specific Hsp90 phosphorylation sites acting as modulators of fungal virulence. Post-translational modifications of Hsp90 could prove valuable in future exploitation as antifungal 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 pH Signaling in Human Fungal Pathogens: a New Target for Antifungal Strategies

2014 ◽  
Vol 13 (3) ◽  
pp. 342-352 ◽  
Author(s):  
Muriel Cornet ◽  
Claude Gaillardin
Keyword(s):  
Mammalian Cells ◽  
Drug Targets ◽  
Fungal Pathogens ◽  
Synergistic Effects ◽  
Pathogenic Fungi ◽  
Antifungal Drugs ◽  
Drug Pressure ◽  
Fungal Virulence ◽  
Content Type

ABSTRACTFungi are exposed to broadly fluctuating environmental conditions, to which adaptation is crucial for their survival. An ability to respond to a wide pH range, in particular, allows them to cope with rapid changes in their extracellular settings. PacC/Rim signaling elicits the primary pH response in both model and pathogenic fungi and has been studied in multiple fungal species. In the predominant human pathogenic fungi, namely,Candida albicans,Aspergillus fumigatus, andCryptococcus neoformans, this pathway is required for many functions associated with pathogenesis and virulence. Aspects of this pathway are fungus specific and do not exist in mammalian cells. In this review, we highlight recent advances in our understanding of PacC/Rim-mediated functions and discuss the growing interest in this cascade and its factors as potential drug targets for antifungal strategies. We focus on both conserved and distinctive features in model and pathogenic fungi, highlighting the specificities of PacC/Rim signaling inC. albicans,A. fumigatus, andC. neoformans. We consider the role of this pathway in fungal virulence, including modulation of the host immune response. Finally, as now recognized for other signaling cascades, we highlight the role of pH in adaptation to antifungal drug pressure. By acting on the PacC/Rim pathway, it may therefore be possible (i) to ensure fungal specificity and to limit the side effects of drugs, (ii) to ensure broad-spectrum efficacy, (iii) to attenuate fungal virulence, (iv) to obtain additive or synergistic effects with existing antifungal drugs through tolerance inhibition, and (v) to slow the emergence of resistant mutants.

scholarly journals Antibacterial Discovery: 21st Century Challenges

Antibiotics ◽  
2020 ◽  
Vol 9 (5) ◽  
pp. 213 ◽  
Author(s):  
Paul S. Hoffman
Keyword(s):  
Drug Resistance ◽  
21St Century ◽  
Drug Targets ◽  
Anaerobic Bacteria ◽  
Multidrug Resistant ◽  
Wide Range ◽  
New Chemical Entities ◽  
Antibiotic Discovery ◽  
Novel Drug ◽  
Novel Drug Targets

It has been nearly 50 years since the golden age of antibiotic discovery (1945–1975) ended; yet, we still struggle to identify novel drug targets and to deliver new chemical classes of antibiotics to replace those rendered obsolete by drug resistance. Despite herculean efforts utilizing a wide range of antibiotic discovery platform strategies, including genomics, bioinformatics, systems biology and postgenomic approaches, success has been at best incremental. Obviously, finding new classes of antibiotics is really hard, so repeating the old strategies, while expecting different outcomes, seems to boarder on insanity. The key questions dealt with in this review include: (1) If mutation based drug resistance is the major challenge to any new antibiotic, is it possible to find drug targets and new chemical entities that can escape this outcome; (2) Is the number of novel chemical classes of antibacterials limited by the number of broad spectrum drug targets; and (3) If true, then should we focus efforts on subgroups of pathogens like Gram negative or positive bacteria only, anaerobic bacteria or other group where the range of common essential genes is likely greater?. This review also provides some examples of existing drug targets that appear to escape the specter of mutation based drug resistance, and provides examples of some intermediate spectrum strategies as well as modern molecular and genomic approaches likely to improve the odds of delivering 21st century medicines to combat multidrug resistant pathogens.

Sign in / Sign up

Export Citation Format

Share Document