Biological Characterization of Prasinomycin, a Phosphorus-containing Antibiotic

Meyers, Edward A.; Miraglia, Gennaro J.; Smith, Dorothy A.; Basch, Harold; Pansy, Felix; Trejo, William H.; Donovick, Richard

doi:10.1128/am.16.4.603-608.1968

“…All experiments were performed using the wildtype C. albicans strain SN250 [62]. The results using SN250 were validated using the C. albicans clinical isolates SC5314 [63] and Strain #0761 (AR0761) (Centers for Disease Control and Prevention (CDC) AR Isolate Bank, Drug Resistance Candida species panel; https://wwwn.cdc.gov/ARIsolateBank/ (access on 5 February 2021). C. albicans cells were recovered from −80 • C glycerol stocks for two days at 30 • C on yeast extract peptone dextrose (YPD) agar plates (1% yeast extract (Thermo Fisher Scientific, Catalog #211929), 2% Bacto peptone (Gibco, Catalog #211677), 2% dextrose (Fisher Scientific, Catalog #D16-3), and 2% agar (Criterion, Catalog #89405-066)).…”

Section: Strains and Mediamentioning

confidence: 99%

Visible Lights Combined with Photosensitizing Compounds Are Effective against Candida albicans Biofilms

Bapat

¹

,

Singh

²

,

Nobile

³

2021

View full text Add to dashboard Cite

Fungal infections are increasing in prevalence worldwide, especially in immunocompromised individuals. Given the emergence of drug-resistant fungi and the fact that there are only three major classes of antifungal drugs available to treat invasive fungal infections, there is a need to develop alternative therapeutic strategies effective against fungal infections. Candida albicans is a commensal of the human microbiota that is also one of the most common fungal pathogens isolated from clinical settings. C. albicans possesses several virulence traits that contribute to its pathogenicity, including the ability to form drug-resistant biofilms, which can make C. albicans infections particularly challenging to treat. Here, we explored red, green, and blue visible lights alone and in combination with common photosensitizing compounds for their efficacies at inhibiting and disrupting C. albicans biofilms. We found that blue light inhibited biofilm formation and disrupted mature biofilms on its own and that the addition of photosensitizing compounds improved its antibiofilm potential. Red and green lights, however, inhibited biofilm formation only in combination with photosensitizing compounds but had no effects on disrupting mature biofilms. Taken together, these results suggest that photodynamic therapy may be an effective non-drug treatment for fungal biofilm infections that is worthy of further exploration.

show abstract

“…For C. albicans (SC5314), Candida dubliniensis (CD36), and Candida glabrata (CBS138), we used the sequenced strains SC5314, CD36, and CBS138/ATCC 2001, respectively. SC5314 was isolated from a patient with disseminated candidiasis prior to 1968 (89–92), CD36 was isolated from the mouth of an Irish HIV patient between 1988 and 1994 (93), and CBS138 is listed as coming from a fecal sample (https://www.atcc.org/products/all/2001.aspx#history). Unless otherwise noted, assays used the same three C. auris isolates (AR-384/MLY1540, clade III; AR-386/MLY1542, clade IV; AR- 387/MLY1543, clade I) to ensure representation of the three clades most associated with serious infections as well as wide distribution of sensitivities to fluconazole and caspofungin.…”

Section: Methodsmentioning

confidence: 99%

Broad sensitivity ofCandida aurisstrains to quinolones and mechanisms of resistance

Lohse

¹

,

Laurie

²

,

Levan

³

et al. 2023

Preprint

0

View full text Add to dashboard Cite

The fungal pathogenCandida aurisrepresents a severe threat to hospitalized patients. Its resistance to multiple classes of antifungal drugs and ability to spread and resist decontamination in health-care settings make it especially dangerous. We screened 1,990 clinically approved and late-stage investigational compounds for the potential to be repurposed as antifungal drugs targetingC. aurisand narrowed our focus to five FDA-approved compounds with inhibitory concentrations under 10 μM forC. aurisand significantly lower toxicity to three human cell lines. These compounds, some of which had been previously identified in independent screens, include three dihalogenated 8-hydroxyquinolines: broxyquinoline, chloroxine, and clioquinol. A subsequent structure-activity study of 32 quinoline derivatives found that 8-hydroxyquinolines, especially those dihalogenated at the C5 and C7 positions, were the most effective inhibitors ofC. auris. To pursue these compounds further, we exposedC. auristo clioquinol in an extended experimental evolution study and found thatC. aurisdeveloped only 2- to 5-fold resistance to the compound. DNA sequencing of resistant strains and subsequent verification by directed mutation in naive strains revealed that resistance was due to mutations in the transcriptional regulatorCAP1(causing upregulation of the drug transporterMDR1) and in the drug transporterCDR1. These mutations had only modest effects on resistance to traditional antifungal agents, and theCDR1mutation renderedC. aurismore sensitive to posaconazole. This observation raises the possibility that a combination treatment involving an 8-hydroxyquinoline and posaconazole might preventC. aurisfrom developing resistance to this established antifungal agent.

show abstract

“…For C. albicans (SC5314), Candida dubliniensis (CD36), and Candida glabrata (CBS138), we used the sequenced strains SC5314, CD36, and CBS138/ATCC 2001, respectively. SC5314 was isolated from a patient with disseminated candidiasis prior to 1968 ( 94 - 97 ), CD36 was isolated from the mouth of an Irish HIV patient between 1988 and 1994 ( 98 ), and CBS138 is listed as coming from a fecal sample ( https://www.atcc.org/products/all/2001.aspx#history ). Unless otherwise noted, assays used the same three C. auris isolates (AR-384/MLY1540, clade III; AR-386/MLY1542, clade IV; AR-387/MLY1543, clade I) to ensure representation of the three clades most associated with serious infections as well as wide distribution of susceptibilities to fluconazole and caspofungin.…”

Section: Methodsmentioning

confidence: 99%

Broad susceptibility of Candida auris strains to 8-hydroxyquinolines and mechanisms of resistance

Lohse

¹

,

Laurie

²

,

Levan

³

et al. 2023

mBio

2

0

View full text Add to dashboard Cite

The fungal pathogen Candida auris represents a severe threat to hospitalized patients. Its resistance to multiple classes of antifungal drugs and ability to spread and resist decontamination in healthcare settings make it especially dangerous. We screened 1,990 clinically approved and late-stage investigational compounds for the potential to be repurposed as antifungal drugs targeting C. auris and narrowed our focus to five Food and Drug Administration (FDA)-approved compounds with inhibitory concentrations under 10 µM for C. auris and significantly lower toxicity to three human cell lines. These compounds, some of which had been previously identified in independent screens, include three dihalogenated 8-hydroxyquinolines: broxyquinoline, chloroxine, and clioquinol. A subsequent structure-activity study of 32 quinoline derivatives found that 8-hydroxyquinolines, especially those dihalogenated at the C5 and C7 positions, were the most effective inhibitors of C. auris . To pursue these compounds further, we exposed C. auris to clioquinol in an extended experimental evolution study and found that C. auris developed only twofold to fivefold resistance to the compound. DNA sequencing of resistant strains and subsequent verification by directed mutation in naive strains revealed that resistance was due to mutations in the transcriptional regulator CAP1 (causing upregulation of the drug transporter MDR1 ) and in the drug transporter CDR1 . These mutations had only modest effects on resistance to traditional antifungal agents, and the CDR1 mutation rendered C. auris more susceptible to posaconazole. This observation raises the possibility that a combination treatment involving an 8-hydroxyquinoline and posaconazole might prevent C. auris from developing resistance to this established antifungal agent. IMPORTANCE The rapidly emerging fungal pathogen Candida auris represents a growing threat to hospitalized patients, in part due to frequent resistance to multiple classes of antifungal drugs. We identify a class of compounds, the dihalogenated 8-hydroxyquinolines, with broad fungistatic ability against a diverse collection of 13 strains of C. auris . Although this compound has been identified in previous screens, we extended the analysis by showing that C. auris developed only modest twofold to fivefold increases in resistance to this class of compounds despite long-term exposure; a noticeable difference from the 30- to 500-fold increases in resistance reported for similar studies with commonly used antifungal drugs. We also identify the mutations underlying the resistance. These results suggest that the dihalogenated 8-hydroxyquinolines are working inside the fungal cell and should be developed further to combat C. auris and other fungal pathogens. Lohse and colleagues characterize a class of compounds that inhibit the fungal pathogen C. auris . Unlike many other antifungal drugs, C. auris does not readily develop resistance to this class of compounds.

show abstract

Biological Characterization of Prasinomycin, a Phosphorus-containing Antibiotic

Cited by 14 publications

References 0 publications

Visible Lights Combined with Photosensitizing Compounds Are Effective against Candida albicans Biofilms

Visible Lights Combined with Photosensitizing Compounds Are Effective against Candida albicans Biofilms

Broad sensitivity ofCandida aurisstrains to quinolones and mechanisms of resistance

Broad susceptibility of Candida auris strains to 8-hydroxyquinolines and mechanisms of resistance

Contact Info

Product

Resources

About