Synthetic arylquinuclidine derivatives exhibit antifungal activity against Candida albicans, Candida tropicalis and Candida parapsilopsis

Ishida, Kelly; Rodrigues, Juliany Cola Fernandes; Cammerer, Simon; Urbina, Julio A.; Gilbert, Ian H.; Souza, Wanderley de; Rozental, Sônia

doi:10.1186/1476-0711-10-3

Cited by 23 publications

(17 citation statements)

References 35 publications

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“…SNP+SHAM treated cells also led to the downregulation of a group of ergosterol biosynthesis pathway genes (Fig 4B). Inhibition of sterol biosynthesis has been shown to lead to an increase in the incidence of lipid droplets [66], which we also observed in SNP+SHAM treated cells. UPC2 , encoding a transcription factor known to activate ergosterol biosynthesis, especially under hypoxic conditions, was upregulated and required for the observed resistance to caspofungin.…”

Section: Discussionsupporting

confidence: 81%

Inhibition of classical and alternative modes of respiration in C. albicans leads to cell wall remodelling and increased macrophage recognition

Duvenage

Walker

Bojarczuk

et al. 2018

Preprint

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The human fungal pathogen C. albicans requires respiratory function for normal growth, morphogenesis and virulence. As such the mitochondria represent an enticing target for the development of new antifungal strategies. This possibility is further bolstered by the presence of fungal specific characteristics. However, respiration in C. albicans, as is the case in many fungal organisms, is facilitated by redundant electron transport mechanisms that makes direct inhibition a challenge. In addition, many chemicals known to target the electron transport chain are highly toxic. Here we make use of chemicals with low toxicity in mammals to efficiently inhibit respiration in C. albicans. We find that use of the Nitric Oxide donor, Sodium Nitroprusside (SNP), and the alternative oxidase inhibitor, SHAM, prevent respiration, lead to a loss in viability and to cell wall rearrangements that increase the rate of uptake by macrophages in vitro and in vivo. We propose that SNP+SHAM treatment leads to transcriptional changes that drive cell wall re-arrangement but which also prime cells to activate transition to hyphal growth. In line with this we find that pre-treatment of C. albicans with SNP+SHAM leads to an increase in virulence. Our data reveals strong links between respiration, cell wall remodelling and activation of virulence factors. Our findings also demonstrate that respiration in C. albicans can be efficiently inhibited with chemicals which are not damaging to the mammalian host, but that we need to develop a deeper understanding of the roles of mitochondria in cellular signalling if they are to be developed successfully as a target for new antifungals.Author SummaryCurrent approaches to tackling fungal infections are limited and new targets must be identified to protect against the emergence of resistant strains. We investigate the potential of targeting mitochondria, organelles required for energy production, growth and virulence, in the yeast human fungal pathogen Candida albicans. Our findings suggest that mitochondria can be targeted using drugs that can be tolerated by humans and that this treatment enhances their recognition by immune cells. However release of C. albicans cells from mitochondrial inhibition appears to activate a stress response that increases traits associated with virulence. Our results make it clear that mitochondria are a valid target for the development of anti-fungal strategies but that we must determine the mechanisms by which they regulate stress signalling and virulence ahead of successful therapeutic advance.

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Section: Discussionsupporting

confidence: 81%

Inhibition of classical and alternative modes of respiration in C. albicans leads to cell wall remodelling and increased macrophage recognition

Duvenage

Walker

Bojarczuk

et al. 2018

Preprint

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“…Also, recent findings showed that antimicrobial compounds may induce an accumulation of lipid droplets in the cytoplasm of Candida spp. (34) and protozoans (35). In Mycobacterium leprae-infected cells, LBs showed a strong ability to fuse, forming giant lipid droplets (36).…”

Section: Discussionmentioning

confidence: 99%

In Vitro and In Vivo Trypanosomicidal Action of Novel Arylimidamides against Trypanosoma cruzi

Guedes-da-Silva

Batista

Meuser

et al. 2016

Antimicrob Agents Chemother

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“…In addition, several arylquinuclidine derivatives such as 96 (Fig. 14) had a MIC 50 of 2 mg/mL for three strains tested, C. albicans, C. tropicalis and C. parapsilopsis [143]. Thus, arylquinuclidines may also be useful as leads for the rational design of new antifungal agents and of novel treatments against multiple drug-resistant candida species.…”

Section: Leismaniasis and Chagasmentioning

confidence: 97%

Squalene Synthase Inhibitors: An Update on the Search for New Antihyperlipidemic and Antiatherosclerotic Agents

Kourounakis

Katselou²,

Matralis³

et al. 2011

CMC

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Atherosclerosis and related heart disease is strongly associated with elevated blood levels of total (and LDL) cholesterol. Due to the widespread incidence as well as severity of this pathological condition, major efforts have been made for the discovery and development of hypocholesteroleamic agents. In the past few decades, HMG-CoA reductase inhibitors (statins) are being extensively used as lipid lowering drugs. These agents act predominantly by inhibiting the enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR) that is the rate limiting step of cholesterol biosynthesis. Both the success as well as drawbacks of HMGRIs, have led to the investigation and design of inhibitors of other (downstream) enzymes involved in the multistep cholesterol biosynthetic pathway. One such class of agents consists of the squalene sythase inhibitors which act at the first and solely committed step towards the biosynthesis of the cholesterol nucleus. This target is considered not to interfere with the biosynthesis of other biologically important molecules and thus a better side-effect profile is expected for these inhibitors. Several classes of squalene synthase inhibitors (SQSIs), such as substrate or transition-state analogues, zaragozic acids or 2,8- dioxabicyclo[3.2.1]octane derivatives, dicarboxylic acid and quinuclidine derivatives, 4,1-benzoxazepine as well as substituted morpholine derivatives, have been studied as potent inhibitors of squalene synthase. So far only one benzoxazepine derivative (TAK-475) has been evaluated in advanced clinical trials. In this article we review the up to date research and literature on the therapeutic potential of this relatively new class of compounds, the drug discovery efforts towards the development of active squalene synthase inhibitors, their activity profile and effectiveness, as well as their structure-activity relationships.

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Synthetic arylquinuclidine derivatives exhibit antifungal activity against Candida albicans, Candida tropicalis and Candida parapsilopsis

Cited by 23 publications

References 35 publications

Inhibition of classical and alternative modes of respiration in C. albicans leads to cell wall remodelling and increased macrophage recognition

Inhibition of classical and alternative modes of respiration in C. albicans leads to cell wall remodelling and increased macrophage recognition

In Vitro and In Vivo Trypanosomicidal Action of Novel Arylimidamides against Trypanosoma cruzi

Squalene Synthase Inhibitors: An Update on the Search for New Antihyperlipidemic and Antiatherosclerotic Agents

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