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Antifungal activity of fused Mannich ketones triggers an oxidative stress response and is Cap1-dependent in Candida albicans.

ABSTRACT: We investigated the antifungal activity of fused Mannich ketone (FMK) congeners and two of their aminoalcohol derivatives. In particular, FMKs with five-membered saturated rings were shown to have minimum inhibitory concentration (MIC90s) ranging from 0.8 to 6 µg/mL toward C. albicans and the closely related C. parapsilosis and C. krusei while having reduced efficacy toward C. glabrata and almost no efficacy against Aspergillus sp. Transcript profiling of C. albicans cells exposed for 30 or 60 min to 2-(morpholinomethyl)-1-indanone, a representative FMK with a five-membered saturated ring, revealed a transcriptional response typical of oxidative stress and similar to that of a C. albicans Cap1 transcriptional activator. Consistently, C. albicans lacking the CAP1 gene was hypersensitive to this FMK, while C. albicans strains overexpressing CAP1 had decreased sensitivity to 2-(morpholinomethyl)-1-indanone. Quantitative structure-activity relationship studies revealed a correlation of antifungal potency and the energy of the lowest unoccupied molecular orbital of FMKs and unsaturated Mannich ketones thereby implicating redox cycling-mediated oxidative stress as a mechanism of action. This conclusion was further supported by the loss of antifungal activity upon conversion of representative FMKs to aminoalcohols that were unable to participate in redox cycles.

SUBMITTER: Rossignol T

PROVIDER: S-EPMC3639977 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Antifungal activity of fused Mannich ketones triggers an oxidative stress response and is Cap1-dependent in Candida albicans.

Rossignol Tristan T Kocsis Béla B Bouquet Orsolya O Kustos Ildikó I Kilár Ferenc F Nyul Adrien A Jakus Péter B PB Rajbhandari Kshitij K Prókai László L d'Enfert Christophe C Lóránd Tamás T

PloS one 20130430 4

We investigated the antifungal activity of fused Mannich ketone (FMK) congeners and two of their aminoalcohol derivatives. In particular, FMKs with five-membered saturated rings were shown to have minimum inhibitory concentration (MIC90s) ranging from 0.8 to 6 µg/mL toward C. albicans and the closely related C. parapsilosis and C. krusei while having reduced efficacy toward C. glabrata and almost no efficacy against Aspergillus sp. Transcript profiling of C. albicans cells exposed for 30 or 60 m ...[more]

PMID: 23646117

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Project description:Candida albicans, a ubiquitous opportunistic fungal pathogen, plays a pivotal role in human health and disease. As a commensal organism, it normally resides harmlessly within the human microbiota. However, under certain conditions, C. albicans can transition into a pathogenic state, leading to various infections collectively known as candidiasis. With the increasing prevalence of immunocompromised individuals and the widespread use of invasive medical procedures, candidiasis has become a significant public health concern. The emergence of drug-resistant strains further complicates treatment options, highlighting the urgent need for alternative therapeutic strategies. Antifungal peptides (AFPs) have gained considerable attention as potential candidates for combating Candida spp. infections. These naturally occurring peptides possess broad-spectrum antimicrobial activity, including specific efficacy against C. albicans. AFPs exhibit several advantageous properties, such as rapid killing kinetics, low propensity for resistance development, and diverse mechanisms of action, making them promising alternatives to conventional antifungal agents. In recent years, extensive research has focused on discovering and developing novel AFPs with improved efficacy and selectivity against Candida species. Advances in biotechnology and synthetic peptide design have enabled the modification and optimization of natural peptides, enhancing their stability, bioavailability, and therapeutic potential. Nevertheless, several challenges must be addressed before AFPs can be widely implemented in clinical practice. These include optimizing peptide stability, enhancing delivery methods, overcoming potential toxicity concerns, and conducting comprehensive preclinical and clinical studies. This commentary presents a short overview of candidemia and AFP; articles and reviews published in the last 10 years were searched on The National Library of Medicine (National Center for Biotechnology Information-NIH-PubMed). The terms used were C. albicans infections, antimicrobial peptides, antifungal peptides, antifungal peptides mechanisms of action, candidemia treatments and guidelines, synthetic peptides and their challenges, and antimicrobial peptides in clinical trials as the main ones. Older publications were cited if they brought some relevant concept or helped to bring a perspective into our narrative. Articles older than 20 years and those that appeared in PubMed but did not match our goal to bring updated information about using antifungal peptides as an alternative to C. albicans infections were not considered.

Project description:Cap1p, a transcription factor of the basic region-leucine zipper family, controls the oxidative stress response in Candida albicans. It was shown that alteration of the C-terminal cysteine-rich domain (CRD) of Cap1p results in nuclear retention and constitutive transcriptional activation. To further characterize the function of Cap1p in C. albicans, we used genome-wide location profiling (ChIP-on-chip), allowing the identification of Cap1p-transcriptional targets in vivo. Location profiling using a tiled-oligonucleotide DNA microarray identified 89 targets that were bound by Cap1p-HA3 or Cap1p-CSE-HA3 (binding ratio â¥ 2-fold, P â¤ 0.01). Strikingly, Cap1p binding was not only detected at the promoter region of its target genes but also at their 3'-end and within their open-reading frame. Overrepresented functional groups of Cap1p targets (P â¤ 0.02) included notably 11 genes involved in response to oxidative stress (CAP1, GLR1, TRX1, others), 13 genes involved in response to drug (PDR16, MDR1, FLU1, others) and 3 genes involved in regulation of nitrogen utilization (orf19.2693, orf19.3121 and GST3). Bioinformatic analyses suggested that Cap1p binds to the DNA motif 5'- MTKASTMA. Transcriptome analyses showed that increased expression of most of Cap1p targets accompanies Cap1p binding at these targets, indicating that Cap1p is a transcriptional activator. We conclude that, in addition to protecting the cell against oxidative stress, Cap1p appears to have other functions including drug resistance and the regulation of nitrogen utilization. The atypical binding pattern of Cap1p suggests that this transcription factor may associate with the transcriptional or the chromatin remodeling machinery to exert its activity. We performed three gene expression profile comparisons: (1) benomyl-induced gene expression in a strain containing wildtype CAP1 (CJD21/PMK-CAP1 +/- benomyl), (2) benomyl-induced gene expression in a strain where CAP1 is disrupted (CJD21/PMK +/- benomyl), and (3) gene expression in a strain containing a hyperactive allele of CAP1 compared to a strain containing wildtype CAP1 (CJD21/PMK-CAP1-CSE vs. CJD21/PMK-CAP1). There were three biological replicates (each drug-treated and untreated strain was grown/treated in three independent experiments). Since our Affymetrix platform requires each sample is hybridized on a separate chip, there is no dye-swapping. For each benomyl-treatment experiment (comparisons 1 and 2 above), the untreated (diluent-treated) samples are the reference samples. For comparison 3, the CJD21-PMK-CAP1 sample is the reference sample.

Project description:UnlabelledFollowing phagocytosis, microbes are exposed to an array of antimicrobial weapons that include reactive oxygen species (ROS) and cationic fluxes. This is significant as combinations of oxidative and cationic stresses are much more potent than the corresponding single stresses, triggering the synergistic killing of the fungal pathogenCandida albicansby "stress pathway interference." Previously we demonstrated that combinatorial oxidative plus cationic stress triggers a dramatic increase in intracellular ROS levels compared to oxidative stress alone. Here we show that activation of Cap1, the major regulator of antioxidant gene expression inC. albicans, is significantly delayed in response to combinatorial stress treatments and to high levels of H2O2 Cap1 is normally oxidized in response to H2O2; this masks the nuclear export sequence, resulting in the rapid nuclear accumulation of Cap1 and the induction of Cap1-dependent genes. Here we demonstrate that following exposure of cells to combinatorial stress or to high levels of H2O2, Cap1 becomes trapped in a partially oxidized form, Cap1(OX-1) Notably, Cap1-dependent gene expression is not induced when Cap1 is in this partially oxidized form. However, while Cap1(OX-1)readily accumulates in the nucleus and binds to target genes following high-H2O2stress, the nuclear accumulation of Cap1(OX-1)following combinatorial H2O2and NaCl stress is delayed due to a cationic stress-enhanced interaction with the Crm1 nuclear export factor. These findings define novel mechanisms that delay activation of the Cap1 transcription factor, thus preventing the rapid activation of the stress responses vital for the survival ofC. albicanswithin the host.ImportanceCombinatorial stress-mediated synergistic killing represents a new unchartered area in the field of stress signaling. This phenomenon contrasts starkly with "stress cross-protection," where exposure to one stress protects against subsequent exposure to a different stress. Previously we demonstrated that the pathogenCandida albicansis acutely sensitive to combinations of cationic and oxidative stresses, because the induction of H2O2-responsive genes is blocked in the presence of cationic stress. We reveal that this is due to novel mechanisms that delay activation of the Cap1 AP-1-like transcription factor, the major regulator of the H2O2-induced regulon. Cap1 becomes trapped in a partially oxidized form following simultaneous exposure to oxidative and cationic stresses. In addition, cationic stress promotes the interaction of Cap1 with the Crm1 nuclear export factor, thus inhibiting its nuclear accumulation. These mechanisms probably explain the potency of neutrophils, which employ multiple stresses to kill fungal pathogens.

Dataset Information

Antifungal activity of fused Mannich ketones triggers an oxidative stress response and is Cap1-dependent in Candida albicans.

Publications

Antifungal activity of fused Mannich ketones triggers an oxidative stress response and is Cap1-dependent in Candida albicans.

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