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Overcoming amphotericin B resistance in Candida auris using the antiemetic drug, rolapitant

ABSTRACT: The emergence of Candida auris poses a significant health challenge that has led to a new era of multidrug-resistant fungal infections. Invasive infections caused by C. auris are usually associated with remarkable morbidity and mortality. For many years, amphotericin B (AmB) remained the most efficient and the last line of treatment against most hard-to-treat fungal infections. However, strains of C. auris possess extraordinary resistance to most antifungal agents, including AmB. In this study, we screened ~2600 FDA-approved drugs and clinical compounds to identify the antiemetic drug rolapitant as a promising enhancer to AmB against C. auris. Rolapitant exhibited potent synergistic interactions with AmB against all tested (29/29) C. auris isolates. In a time-kill assay, rolapitant restored the fungicidal activity of AmB within 4 h. Additionally, the synergistic relationship between rolapitant and AmB was observed against other medically crucial Candida, Cryptococcus and Aspergillus species with ΣFICI that ranged from 0.16 to 0.5. In a transcriptomic study, ion transporters and ATP generation were identified as primary pathways impacted in C. auris AR0390 cells exposed to rolapitant. An ATP luminescence assay confirmed that rolapitant, at sub-inhibitory concentrations, significantly interfered with ATP production in C. auris. Moreover, rolapitant enhanced the in vivo activity of AmB in a mouse model of disseminated C. auris infection, as the combination reduced the fungal burden in murine kidneys by ~1 log (~90%) colony forming units. Our findings warrant further investigation of using rolapitant to overcome AmB resistance in C. auris and other fungal species.

ORGANISM(S): Candidozyma auris

PROVIDER: GSE263806 | GEO | 2024/09/26

REPOSITORIES: GEO

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Lansoprazole interferes with fungal respiration and acts synergistically with amphotericin B against multidrug-resistant Candida auris

Project description:Candida auris has emerged as a problematic fungal pathogen associated with high morbidity and mortality. Amphotericin B (AmB) is the most effective antifungal used to treat invasive fungal candidiasis, with resistance rarely observed among clinical isolates. However, C. auris possesses extraordinary resistant profiles against all available antifungal drugs, including AmB. In our pursuit of potential solutions, we conducted a screening of a panel of 727 FDA-approved drugs and identified the proton pump inhibitor lansoprazole (LNP) as a potent enhancer of AmB’s activity against C. auris. LNP also potentiates the antifungal activity of AmB against other medically important species of Candida and Cryptococcus. Our investigations into the mechanism of action unveiled that LNP metabolite(s) interact with a crucial target in the mitochondrial respiratory chain (complex III, known as cytochrome bc1). This interaction increases oxidative stress within fungal cells. Our results demonstrated the critical role of an active respiratory function in the antifungal activity of LNP. Most importantly, LNP restored the efficacy of AmB in an immunocompromised mouse model, resulting in a 1.7-log (~98%) CFU reduction in the burden of C. auris in the kidneys. Our findings strongly advocate for a thorough and comprehensive evaluation of LNP as a cytochrome bc1 inhibitor for combating drug-resistant C. auris infections.

2024-03-13 | GSE244094 | GEO

Comparative Transcriptomics Reveal Determinants of Amphotericin B Resistance in Candida auris

Project description:Candida auris is an emerging multidrug-resistant human fungal pathogen often refractory to treatment by all classes of antifungal drugs. Amphotericin B (AmB) is a fungicidal drug that, despite its toxic side effects, remains a drug of choice for the treatment of drug-resistant fungal infections, including those caused by C. auris. However, the molecular mechanisms underlying AmB resistance are poorly understood. In this study, we present data that suggests membrane lipid alterations and chromatin modifications are critical processes that contribute to or cause adaptive AmB resistance in clinical C. auris isolates. To determine the plausible cause of increased AmB resistance, we performed RNA-seq of AmB-resistant and sensitive C. auris isolates. Remarkably, AmB-resistant strains show a pronounced enrichment of genes involved in lipid and ergosterol biosynthesis, adhesion, drug transport as well as chromatin remodeling. The transcriptomics data confirm increased adhesion and reduced lipid membrane permeability of AmB-resistant strains compared to the sensitive isolates. The AmB-resistant strains also display hyper-resistance to cell wall perturbing agents, including congo red, calcofluor white and caffeine. Additionally, we noticed an increased phosphorylation of Mkc1 cell integrity MAP kinase upon AmB treatment. Collectively, these data identify differences in the transcriptional landscapes of AmB-resistant vs AmB-senstive isolates, and provide a framework for the mechanistic understanding of AmB resistance in C. auris.

2022-05-02 | GSE190920 | GEO

Potent synergistic interactions between lopinavir and azole antifungal drugs against emerging multidrug-resistant Candida auris

Project description:The limited number of antifungals and the emergence of multidrug-resistant Candida auris pose a significant challenge to human medicine. Here, we utilized combinatorial drug therapy as an approach to augment the activity of current azole antifungals against C. auris. We evaluated the fluconazole chemosensitization activity of 1547 FDA-approved drugs and clinical molecules against an azole-resistant strain of C. auris. This led to the discovery that lopinavir, an antiviral drug, is a potent agent capable of sensitizing C. auris to the effect of azole antifungals. At a therapeutically achievable concentration (4-8 µg/ml), lopinavir exhibited potent synergistic interactions with azole drugs, particularly with itraconazole, against C. auris (ΣFICI ranged from 0.05-0.50). The lopinavir/itraconazole combination enhanced the survival rate of C. auris-infected Caenorhabditis elegans by 90% and reduced the fungal burden in infected nematodes by 88.5% (p < 0.05). Moreover, lopinavir enhanced the antifungal activity of itraconazole against other medically important Candida species including C. albicans, C. tropicalis, C. glabrata, C. tropicalis, and C. parapsilosis. Comparative transcriptomic profiling revealed that lopinavir interferes with glucose permeation and ATP synthesis. This compromises the function of the efflux pumps presents in C. auris enhancing sensitivity to azole antifungals, as demonstrated by Nile red efflux assays. This study presents lopinavir as a novel, potent and broad-spectrum azole chemosensitizing agent that warrants further investigation against recalcitrant Candida infections.

2020-10-06 | GSE148341 | GEO

Aprepitant, an antiemetic agent, displays potent synergistic interactions with azole drugs against emerging multidrug-resistant Candida auris

Project description:Combination therapies can be a promising tool to augment the antifungal activity of azole drugs against resistant Candida species. Here, we report the interaction between aprepitant, an antiemetic agent, and azole drugs against different Candida species including the emerging multidrug-resistant C. auris. Particularly, aprepitant enhanced the antifungal activity of itraconazole against C. auris by reducing its minimum inhibitory concentration (MIC) by 2-8 folds. Using Caenorhabditis elegans as an in vivo infection model, the aprepitant/itraconazole combination significantly prolonged the survival of the infected nematodes by ~90% and reduced the fungal burden by ~92% relative to the untreated control. Interestingly, the aprepitant/itraconazole combination exerted a potent fungicidal activity against both planktonic and adherent C. auris biofilms. Further, aprepitant/itraconazole displayed broad-spectrum synergistic interactions against other medically important Candida species including C. albicans, C. krusie, C. tropicalis, and C. parapsilosis (ƩFICI ranged from 0.08 to 031). Comparative transcriptomic profiling indicated aprepitant/itraconazole interferes significantly with metal ions homeostasis and compromises the ROS (reactive oxygen species) detoxification ability of C. auris. This study presents aprepitant as a novel, potent and broad-spectrum azole chemosensitizing agent that warrants further investigation.

2020-10-19 | GSE148749 | GEO

Transcriptomics analysis of amphotericin B and lactoferrin drug synergy in Cryptococcus neoformans H99

2019-09-08 | GSE130375 | GEO

Candida auris infection of human whole blood

Project description:To mimic the initial phases of systemic Candida infections with dissemination via the bloodstream, we used an ex vivo whole blood infection model. Dual TP of C. auris in blood gave insights into fungal adaptations and survival mechanisms as well as the host response to the infection.

2022-01-12 | GSE179000 | GEO

Effect of amphotericin B on Aspergillus fumigatus

Project description:Amphotericin B (AMB) is the most widely used polyene antifungal drug for the treatment of systemic fungal infections including invasive aspergillosis. We aimed to understand molecular targets of AMB in Aspergillus fumigatus (Afu) by genomic approaches. Amphotericin B (AMB) is the most widely used polyene antifungal drug for the treatment of systemic fungal infections including invasive aspergillosis. We aimed to understand molecular targets of AMB in Aspergillus fumigatus (Afu) by microarray and proteomic methods. Keywords: Aspergillus fumigatus treated with amphotericin B for 24 hours Experiment was performed in dye swap manner from two different biological replicates

2010-05-26 | E-GEOD-10505 | biostudies-arrayexpress

High-throughput RNA Sequencing of BMDM of Mus musculus stimulated by C. auris or C. albicans

Project description:Candida auris has been globally recognized as a multidrug-resistant human fungal pathogen that contributes for the worldwide occurrence of nosocomial outbreaks. It has been reported that C. auris was able to avoid neutrophil attack, suggestive of an impaired innate immune response. Whether C. auris evades the innate immune recognition of BMDM (bone marrow derived macrophage) remains poorly understood, and as for well-known Candida species -C. albicans, it can trigger immune response. To determine whether occurs difference between immune response stimulated by C. auris or C. albicans, we performed mRNA-seq of BMDM stimulated by C. auris or C. albicans.

2022-05-21 | GSE203508 | GEO

Identification of the most immunoreactive antigens of Candida auris to sera from infected mice

Project description:Candida auris is a recently found pathogenic yeast that causes systemic infections, showing a high mortality rate. The delay on making a correct diagnosis of C. auris is a current problem in the healthcare system setting. As immunoproteomics studies are important to identify immunoreactive proteins for new diagnostic strategies, in this study immunocompetent murine systemic infections caused by non-aggregative and aggregative phenotypes of C. auris, and by Candida albicans and Candida haemulonii were carried out, and the obtained sera were used to study their immunoreactivity against C. auris proteins. The aim was to identify the most immunoreactive antigens of this yeast. Thirteen spots were recognized by sera from mice infected with both C. auris phenotypes and analyzed by mass spectrometry. They corresponded to enolase, phosphoglycerate kinase, glyceraldehyde 3-phosphate dehydrogenase and phosphoglycerate mutase. These four proteins seem to be also recognized by sera obtained from human patients with disseminated C. auris infection, but not by sera obtained from mice infected with other fungi such as C. albicans or Aspergillus fumigatus. In conclusion, this study showed that the identified proteins could be potential candidates to be studied as new diagnostic or even therapeutic targets for C. auris.

2024-06-23 | PXD049077 | Pride

Transcriptome and network analyses in Saccharomyces cerevisiae reveal that amphotericin B and lactoferrin synergy disrupt metal homeostasis and stress response

Project description:Invasive fungal infections (IFIs) are difficult to treat. Few effective antifungal drugs are available and many have problems with toxicity, efficacy and drug-resistance. To overcome these challenges, existing therapies may be enhanced using more than one agent acting in synergy. Previously, we have found amphotericin B (AMB) and the iron chelator, lactoferrin (LF), were synergistic against Cryptococcus neoformans and Saccharomyces cerevisiae. This study investigates the mechanism of AMB+LF synergy, using RNA-seq and network analyses. Genes involved in iron homeostasis showed increased expression upon treatment with AMB alone. Unexpectedly, AMB+LF treatment did not lead to increased expression of iron or zinc homeostasis genes however we observed decreased expression of oxidative stress response genes. Addition of iron or zinc to AMB+LF treated cells did not rescue the synergy, supporting the likelihood that the mechanism of synergy involves more than iron and zinc chelation. We clustered genes based on patterns of co-expression and found by network analysis that many genes involved in iron and zinc homeostasis, which have dysregulated expression upon AMB+LF treatment, are targets of transcription factors Aft1p and Zap1p. Hypothesizing that these might play a key role in the synergistic response, knock-out mutants of Aft1 and Zap1 were tested for increased sensitivity to AMB and oxidative stress. Both mutants showed hypersensitivity towards these treatments. Our results suggest the mechanism of AMB+LF synergy involves disruption to oxidative stress response, in addition to chelation of iron and zinc. Since Zap1 is conserved in C. neoformans and contains a putative drug binding domain, we suggest novel Zap1 binding molecules could be combined with existing antifungals to serve as synergistic antifungal treatments for this species.

2016-12-04 | GSE80357 | GEO

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