scholarly journals Antifungal Resistance, Metabolic Routes as Drug Targets, and New Antifungal Agents: An Overview about Endemic Dimorphic Fungi

2017 ◽  
Vol 2017 ◽  
pp. 1-16 ◽  
Author(s):  
Juliana Alves Parente-Rocha ◽  
Alexandre Melo Bailão ◽  
André Correa Amaral ◽  
Carlos Pelleschi Taborda ◽  
Juliano Domiraci Paccez ◽  
...  
Keyword(s):  
Drug Targets ◽  
Antifungal Agents ◽  
Fungal Infections ◽  
Public Health Problem ◽  
Antifungal Drugs ◽  
Fungal Resistance ◽  
Immunocompromised Patients ◽  
Dimorphic Fungi ◽  
Novel Drug ◽  
Novel Drug Targets

Diseases caused by fungi can occur in healthy people, but immunocompromised patients are the major risk group for invasive fungal infections. Cases of fungal resistance and the difficulty of treatment make fungal infections a public health problem. This review explores mechanisms used by fungi to promote fungal resistance, such as the mutation or overexpression of drug targets, efflux and degradation systems, and pleiotropic drug responses. Alternative novel drug targets have been investigated; these include metabolic routes used by fungi during infection, such as trehalose and amino acid metabolism and mitochondrial proteins. An overview of new antifungal agents, including nanostructured antifungals, as well as of repositioning approaches is discussed. Studies focusing on the development of vaccines against antifungal diseases have increased in recent years, as these strategies can be applied in combination with antifungal therapy to prevent posttreatment sequelae. Studies focused on the development of a pan-fungal vaccine and antifungal drugs can improve the treatment of immunocompromised patients and reduce treatment costs.

scholarly journals Acylhydrazones as Antifungal Agents Targeting the Synthesis of Fungal Sphingolipids

2018 ◽  
Vol 62 (5) ◽  
Author(s):  
Cristina Lazzarini ◽  
Krupanandan Haranahalli ◽  
Robert Rieger ◽  
Hari Krishna Ananthula ◽  
Pankaj B. Desai ◽  
...  
Keyword(s):  
Mammalian Cells ◽  
Antifungal Agents ◽  
Fungal Infections ◽  
Antifungal Drugs ◽  
Fungal Resistance ◽  
Content Type ◽  
Highly Active ◽  
Pharmacokinetic Properties ◽  
Pass Through

ABSTRACTThe incidence of invasive fungal infections has risen dramatically in recent decades. Current antifungal drugs are either toxic, likely to interact with other drugs, have a narrow spectrum of activity, or induce fungal resistance. Hence, there is a great need for new antifungals, possibly with novel mechanisms of action. Previously our group reported an acylhydrazone called BHBM that targeted the sphingolipid pathway and showed strong antifungal activity against several fungi. In this study, we screened 19 derivatives of BHBM. Three out of 19 derivatives were highly active againstCryptococcus neoformansin vitroand had low toxicity in mammalian cells. In particular, one of them, called D13, had a high selectivity index and showed better activity in an animal model of cryptococcosis, candidiasis, and pulmonary aspergillosis. D13 also displayed suitable pharmacokinetic properties and was able to pass through the blood-brain barrier. These results suggest that acylhydrazones are promising molecules for the research and development of new antifungal agents.

scholarly journals Genetic Analysis of Azole Resistance by Transposon Mutagenesis in Saccharomyces cerevisiae

1999 ◽  
Vol 43 (11) ◽  
pp. 2731-2735 ◽  
Author(s):  
D. P. Kontoyiannis
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Drug Targets ◽  
Molecular Mechanisms ◽  
Screening Tool ◽  
Transposon Mutagenesis ◽  
Antifungal Drugs ◽  
Azole Resistance ◽  
Recessive Mutations ◽  
Novel Drug ◽  
Novel Drug Targets

ABSTRACT The increasing resistance of Candida species to fluconazole is cause for concern. To determine the molecular mechanisms involved in resistance to fluconazole, I used a scheme of transposon mutagenesis in Saccharomyces cerevisiae, a genetically tractable yeast that is closely related to Candida albicans. This technique, which permits the generation and analysis of multiple random Tn3::LEU2::lacZfusions, can be used as a disruption mutagen (N. B. Burns et al., Genes Dev. 8:1087–1105, 1994). By using the Tn3::LEU2::lacZlibrary as a disruption mutagen, I found recessive mutations in genes that were previously found to be involved in azole resistance, e.g.,PDR5 and CPR1, and in genes previously found to be involved in azole sensitivity, e.g., ERG3. This approach also enabled me to identify recessive mutations in three genes not previously known to be involved in azole sensitivity. Two of the genes,ADA3 and SPT7, are general transcriptional regulators; the third, YMR034c, is a putative sterol transporter. Finally, by screening the Tn3::LEU2::lacZlibrary for lacZ fusions induced by a low concentration of fluconazole, I identified genes known to be induced by azoles as well as a variety of other genes not previously known to be induced by the drug. In conclusion, transposon mutagenesis is a promising screening tool for use in identifying novel drug targets and in uncovering the mechanisms involved in the response of S. cerevisiae to antifungal drugs.

In vitro antifungal and fungicidal activities and erythrocyte toxicities of cyclic lipodepsinonapeptides produced by Pseudomonas syringae pv. syringae.

1996 ◽  
Vol 40 (12) ◽  
pp. 2710-2713 ◽  
Author(s):  
K N Sorensen ◽  
K H Kim ◽  
J Y Takemoto
Keyword(s):  
Pseudomonas Syringae ◽  
Antifungal Agents ◽  
Fungal Infections ◽  
Antifungal Drugs ◽  
Fungal Resistance ◽  
Broth Microdilution ◽  
Antifungal Activities ◽  
Syringomycin E ◽  
Lead Compounds

Recent increases in fungal infections, the few available antifungal drugs, and increasing fungal resistance to the available antifungal drugs have resulted in a broadening of the search for new antifungal agents. Strains of Pseudomonas syringae pv. syringae produce cyclic lipodepsinonapeptides with antifungal activity. The in vitro antifungal and fungicidal activities of three cyclic lipodepsinonapeptides (syringomycin E, syringotoxin B, and syringostatin A) against medically important isolates were evaluated by a standard broth microdilution susceptibility method. Erythrocyte toxicities were also evaluated. All three compounds showed broad antifungal activities and fungicidal actions against most of the fungi tested. Overall, the cyclic lipodepsinonapeptides were more effective against yeasts than against the filamentous fungi. Syringomycin E and syringostatin A had very similar antifungal activities (2.5 to > 40 micrograms/ml) and erythrocyte toxicities. Syringotoxin B was generally less active (0.8 to 200 micrograms/ml) than syringomycin E and syringostatin A against most fungi and was less toxic to erythrocytes. With opportunities for modification, these compounds are potential lead compounds for improved antifungal agents.

scholarly journals Potency of Olorofim (F901318) Compared to Contemporary Antifungal Agents against Clinical Aspergillus fumigatus Isolates and Review of Azole Resistance Phenotype and Genotype Epidemiology in China

2021 ◽  
Vol 65 (5) ◽  
Author(s):  
Huilin Su ◽  
Min Zhu ◽  
Clement Kin-Ming Tsui ◽  
Henrich van der Lee ◽  
Marlou Tehupeiory-Kooreman ◽  
...  
Keyword(s):  
Aspergillus Fumigatus ◽  
Drug Targets ◽  
Antifungal Agents ◽  
Single Point ◽  
Resistance Mechanism ◽  
Antifungal Drugs ◽  
Single Point Mutation ◽  
Content Type ◽  
Novel Drug

ABSTRACT Triazole resistance in Aspergillus fumigatus is an increasing worldwide problem that causes major challenges in the management of aspergillosis. New antifungal drugs are needed, with novel targets, that are effective in triazole-resistant infection. In this study, we retrospectively evaluated the potency of the novel drug olorofim compared to contemporary antifungal agents against 111 clinical A. fumigatus isolates collected from Huashan Hospital, Shanghai, China, using EUCAST methodology, and we reviewed the literature on triazole-resistant A. fumigatus (TRAF) published between 1966 and 2020 in China. Olorofim was active in vitro against all tested A. fumigatus isolates, with a MIC90 of 0.031 mg/liter (range, 0.008 to 0.062 mg/liter). For 4 triazole-resistant A. fumigatus isolates, the olorofim MIC ranged between 0.016 and 0.062 mg/liter. The reported rates of TRAF in China are 2.5 to 5.56% for clinical isolates and 0 to 1.4% for environmental isolates. TR34/L98H/S297T/F495I is the predominant resistance mechanism, followed by TR34/L98H. Non-TR-mediated TRAF isolates, mostly harboring a cyp51A single point mutation, showed greater genetic diversity than TR-mediated resistant isolates. Resistance due to TR34/L98H and TR34/L98H/S297T/F495I mutations among TRAF isolates might have evolved from separate local isolates in China. Continuous isolation of TRAF in China underscores the need for systematic resistance surveillance as well as the need for novel drug targets, such as olorofim.

Novel drug targets in 2019

2020 ◽  
Vol 19 (5) ◽  
pp. 300-300 ◽  
Author(s):  
Sorin Avram ◽  
Liliana Halip ◽  
Ramona Curpan ◽  
Tudor I. Oprea
Keyword(s):  
Drug Targets ◽  
Novel Drug ◽  
Novel Drug Targets

Potential of Nanoparticles in Combating Candida Infections

2019 ◽  
Vol 16 (5) ◽  
pp. 478-491 ◽  
Author(s):  
Faizan Abul Qais ◽  
Mohd Sajjad Ahmad Khan ◽  
Iqbal Ahmad ◽  
Abdullah Safar Althubiani
Keyword(s):  
Targeted Delivery ◽  
Recent Progress ◽  
Antifungal Agents ◽  
Fungal Infections ◽  
Fold Increase ◽  
Antifungal Drugs ◽  
Low Toxicity ◽  
Candida Infections ◽  
Made In

Aims: The aim of this review is to survey the recent progress made in developing the nanoparticles as antifungal agents especially the nano-based formulations being exploited for the management of Candida infections. Discussion: In the last few decades, there has been many-fold increase in fungal infections including candidiasis due to the increased number of immunocompromised patients worldwide. The efficacy of available antifungal drugs is limited due to its associated toxicity and drug resistance in clinical strains. The recent advancements in nanobiotechnology have opened a new hope for the development of novel formulations with enhanced therapeutic efficacy, improved drug delivery and low toxicity. Conclusion: Metal nanoparticles have shown to possess promising in vitro antifungal activities and could be effectively used for enhanced and targeted delivery of conventionally used drugs. The synergistic interaction between nanoparticles and various antifungal agents have also been reported with enhanced antifungal activity.

scholarly journals Identification of Polo-like kinases as potential novel drug targets for influenza A virus

2017 ◽  
Vol 7 (1) ◽  
Author(s):  
Marie O. Pohl ◽  
Jessica von Recum-Knepper ◽  
Ariel Rodriguez-Frandsen ◽  
Caroline Lanz ◽  
Emilio Yángüez ◽  
...  
Keyword(s):  
Influenza A Virus ◽  
Drug Targets ◽  
Influenza A ◽  
Novel Drug ◽  
Novel Drug Targets
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