An oxindole efflux inhibitor potentiates azoles and impairs virulence in the fungal pathogen Candida auris

Iyer, Kali R.; Camara, Kaddy; Daniel-Ivad, Martin; Trilles, Richard; Pimentel‐Elardo, Sheila Marie; Fossen, Jen; Marchillo, Karen; Liu, Zhongle; Singh, Shakti; Muñoz, José F.; Kim, Sang Hu; Porco, John A.; Cuomo, Christina A.; Williams, Noelle S.; Ibrahim, Ashraf S.; Edwards, John E.; Andes, David R.; Nodwell, Justin R.; Brown, Lauren E.; Whitesell, Luke; Robbins, Nicole; Cowen, Leah E.

doi:10.1038/s41467-020-20183-3

Cited by 51 publications

(57 citation statements)

References 70 publications

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Section: Resultsmentioning

confidence: 99%

“…Many Clade III isolates, including B11221, contain an N647T single nucleotide polymorphism (SNP) in MRR1a (25, 105). In (105), this SNP was proposed to be a gain-of-function mutation due to the resistance of Clade III isolates against azoffluxin, a novel antifungal compound that inhibits expression and activity of C. auris efflux pumps. As a first step to determine if there were activity differences between the Mrr1a variant that was found Clade III strains was different from that encoded by the alleles found in Clade I, II, and IV strains, we compared MG sensitivity of B11221 to that of Clade I isolate AR0390.…”

Section: Resultsmentioning

confidence: 99%

“…These differences were explained by our finding that MRR1a from B11221 encoded a higher activity variant than that from AR0390 as evidenced by a higher FLZ MIC, higher expression of MDR1 and MGD1, and higher MG resistance in the strain expressing CauMRR1a N647T compared to the isogenic strain expressing CauMRR1a. The allele from B11221, which contains an N647T amino acid substitution (25,105) which is in the central region of the regulator where other gain of function substitutions have been found. Both alleles result in induction of MDR1 and MGD1 in response to BEN but not to MG in C. lusitaniae, suggesting that these two compounds activate Mrr1dependent transcription through different mechanisms.…”

Section: Discussionmentioning

confidence: 99%

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Transcriptional response of Candida auris to the Mrr1 inducers methylglyoxal and benomyl

Biermann

Hogan

2022

Preprint

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Candida auris is an urgent threat to human health due to its rapid spread in healthcare settings and its repeated development of multidrug resistance. Diseases that put individuals at a higher risk for C. auris infection, such as diabetes, kidney failure, or immunocompromising conditions, are associated with elevated levels of methylglyoxal (MG), a reactive dicarbonyl compound derived from several metabolic processes. In other Candida species, expression of MG reductase enzymes that catabolize and detoxify MG are controlled by Mrr1, a multidrug resistance-associated transcription factor, and MG induces Mrr1 activity. Here, we used transcriptomics and genetic assays to determine that C. auris MRR1a contributes to MG resistance, and that the main Mrr1a targets are an MG reductase and MDR1, which encodes an drug efflux protein. The C. auris Mrr1a regulon is smaller than Mrr1 regulons described in other species. In addition to MG, benomyl (BEN), a known Mrr1 stimulus, induces C. auris Mrr1 activity, and characterization of the MRR1a-dependent and independent transcriptional responses revealed substantial overlap in genes that were differentially expressed in response to each compound. Additionally, we found that an MRR1 allele specific to one C. auris phylogenetic clade, clade III, encodes a hyperactive Mrr1 variant, and this activity correlated with higher MG resistance. C. auris MRR1a alleles were functional in Candida lusitaniae and were inducible by BEN, but not by MG, suggesting that the two Mrr1 inducers act via different mechanisms. Together, the data presented in this work contribute to the understanding Mrr1 activity and MG resistance in C. auris.ImportanceCandida auris is a fungal pathogen that has spread since its identification in 2009 and is of concern due to its high incidence of resistance against multiple classes of antifungal drugs. In other Candida species, the transcription factor Mrr1 plays a major role in resistance against azole antifungals and other toxins. More recently, Mrr1 has been recognized to contribute to resistance to methylglyoxal (MG), a toxic metabolic byproduct. Here, we show that C. auris MRR1a, the closest ortholog to MRR1 in other species, contributes to resistance to MG, and that Mrr1a strongly co-regulates expression of MGD1, encoding a methylglyoxal reductase enzyme and MDR1, encoding an efflux protein involved in resistance to azole drugs, antimicrobial peptides and bacterial products. We found that one major clade of C. auris has a constitutively active Mrr1 despite high azole resistance due to other mutations, and that this high Mrr1a activity correlates with higher MG resistance. Finally, we gain insights into the activities of MG and another Mrr1 inducer, benomyl, to better understand C. auris regulation of phenotypes relevant in vivo.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Transcriptional response of Candida auris to the Mrr1 inducers methylglyoxal and benomyl

Biermann

Hogan

2022

Preprint

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“…Azoffluxin, due to its strong synergistic interaction with fluconazole against a resistant strain of C. auris Ci6684 was identified ( Figure 10). Azoffluxin enhances azole efficacy in a Cdr1-dependent manner [72].…”

Section: Combination Of New Compounds and Old Drug: In Vitro Resultsmentioning

confidence: 99%

Promising Drug Candidates and New Strategies for Fighting against the Emerging Superbug Candida auris

et al. 2021

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Invasive fungal infections represent an expanding threat to public health. During the past decade, a paradigm shift of candidiasis from Candida albicans to non-albicans Candida species has fundamentally increased with the advent of Candida auris. C. auris was identified in 2009 and is now recognized as an emerging species of concern and underscores the urgent need for novel drug development strategies. In this review, we discuss the genomic epidemiology and the main virulence factors of C. auris. We also focus on the different new strategies and results obtained during the past decade in the field of antifungal design against this emerging C. auris pathogen yeast, based on a medicinal chemist point of view. Critical analyses of chemical features and physicochemical descriptors will be carried out along with the description of reported strategies.

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“…screened 2454 small molecules against C. auris and identified a bis -benzodioxolylindolinone CMLD012336, a 3,3-diarylated oxindole (also called azoffluxin), which showed synergistic interaction with fluconazole against a resistant strain of C. auris . Mechanistically, azoffluxin increased fluconazole sensitivity in both C. auris and C. albicans by inhibiting efflux pump CDR1 ( Iyer et al., 2020 ). Another compound screened from a series of synthesized cyclobutene-dione (squarile) small molecules library, namely compound A, also showed inhibitory effect on MFS efflux pump CaMdr1p, and thus sensitized AD/CaMDR1 to FLC ( Keniya et al., 2015 ).…”

Section: Small Molecules That Inhibit Keystone Bacteria Associated Wi...mentioning

confidence: 99%

The Application of Small Molecules to the Control of Typical Species Associated With Oral Infectious Diseases

Shen

Lyu

Zhang

et al. 2022

Front. Cell. Infect. Microbiol.

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Oral microbial dysbiosis is the major causative factor for common oral infectious diseases including dental caries and periodontal diseases. Interventions that can lessen the microbial virulence and reconstitute microbial ecology have drawn increasing attention in the development of novel therapeutics for oral diseases. Antimicrobial small molecules are a series of natural or synthetic bioactive compounds that have shown inhibitory effect on oral microbiota associated with oral infectious diseases. Novel small molecules, which can either selectively inhibit keystone microbes that drive dysbiosis of oral microbiota or inhibit the key virulence of the microbial community without necessarily killing the microbes, are promising for the ecological management of oral diseases. Here we discussed the research progress in the development of antimicrobial small molecules and delivery systems, with a particular focus on their antimicrobial activity against typical species associated with oral infectious diseases and the underlying mechanisms.

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An oxindole efflux inhibitor potentiates azoles and impairs virulence in the fungal pathogen Candida auris

Cited by 51 publications

References 70 publications

Transcriptional response of Candida auris to the Mrr1 inducers methylglyoxal and benomyl

Transcriptional response of Candida auris to the Mrr1 inducers methylglyoxal and benomyl

Promising Drug Candidates and New Strategies for Fighting against the Emerging Superbug Candida auris

The Application of Small Molecules to the Control of Typical Species Associated With Oral Infectious Diseases

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