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International Journal of Oral Science Sep 2023Candida albicans is the most abundant fungal species in oral cavity. As a smart opportunistic pathogen, it increases the virulence by switching its forms from yeasts to...
Candida albicans is the most abundant fungal species in oral cavity. As a smart opportunistic pathogen, it increases the virulence by switching its forms from yeasts to hyphae and becomes the major pathogenic agent for oral candidiasis. However, the overuse of current clinical antifungals and lack of new types of drugs highlight the challenges in the antifungal treatments because of the drug resistance and side effects. Anti-virulence strategy is proved as a practical way to develop new types of anti-infective drugs. Here, seven artemisinins, including artemisinin, dihydroartemisinin, artemisinic acid, dihydroartemisinic acid, artesunate, artemether and arteether, were employed to target at the hyphal development, the most important virulence factor of C. albicans. Artemisinins failed to affect the growth, but significantly inhibited the hyphal development of C. albicans, including the clinical azole resistant isolates, and reduced their damage to oral epithelial cells, while arteether showed the strongest activities. The transcriptome suggested that arteether could affect the energy metabolism of C. albicans. Seven artemisinins were then proved to significantly inhibit the productions of ATP and cAMP, while reduced the hyphal inhibition on RAS1 overexpression strain indicating that artemisinins regulated the Ras1-cAMP-Efg1 pathway to inhibit the hyphal development. Importantly, arteether significantly inhibited the fungal burden and infections with no systemic toxicity in the murine oropharyngeal candidiasis models in vivo caused by both fluconazole sensitive and resistant strains. Our results for the first time indicated that artemisinins can be potential antifungal compounds against C. albicans infections by targeting at its hyphal development.
Topics: Animals; Mice; Candida albicans; Candidiasis, Oral; Antifungal Agents; Hyphae; Artemisinins
PubMed: 37699886
DOI: 10.1038/s41368-023-00245-0 -
Emerging Microbes & Infections Dec 2023has emerged as a serious threat of public health and caused global epidemic due to multi-drug resistance, remarkable transmissibility and high mortality. To tackle the...
has emerged as a serious threat of public health and caused global epidemic due to multi-drug resistance, remarkable transmissibility and high mortality. To tackle the challenging super fungus, novel benzoanilide antifungal agents were discovered by an integrated strategy of phenotypic screen, hit optimization, antifungal assays and mechanism exploration. The most promising compound showed potent and efficacy against infection. Mechanism investigation revealed that compound blocked the biosynthesis of virulence factors and fungal cell walls through the inhibition of glycosylphosphatidylinositol (GPI) and GPI-anchored proteins. Thus, compound represents a promising lead compound to combat drug-resistant candidiasis.
Topics: Humans; Candida; Candida auris; Antifungal Agents; Candidiasis, Invasive; Microbial Sensitivity Tests
PubMed: 37102336
DOI: 10.1080/22221751.2023.2208687 -
Emerging Microbes & Infections Dec 2023Genomes of strains of the zoophilic dermatophyte from invasive (disseminated and subcutaneous) and noninvasive (tinea capitis) infections were compared. Especially the...
Genomes of strains of the zoophilic dermatophyte from invasive (disseminated and subcutaneous) and noninvasive (tinea capitis) infections were compared. Especially the disseminated strain showed significant syntenic rearrangements, including multiple translocations and inversions, and numerous SNPs and Indels in comparison to the noninvasive strain. In transcriptome analysis, both invasive strains were enriched for GO pathways related to components of the membrane, iron binding and heme binding, which possibly enables them to invade deeper into dermis and blood vessels. At 37 °C, invasive strains showed gene expression enriched for DNA replication, mismatch repair, N-glycan biosynthesis and ribosome biogenesis. The invasive strains were slightly less susceptible to multiple antifungal agents suggesting that acquired elevated drug resistance might be involved in the refractory disease courses. Patient with disseminated infection failed to respond to a combined antifungal treatment with itraconazole, terbinafine, fluconazole and posaconazole.
Topics: Humans; Transcriptome; Tinea Capitis; Microsporum; Antifungal Agents
PubMed: 37288745
DOI: 10.1080/22221751.2023.2219346 -
PLoS Pathogens Nov 2023
Topics: Female; Humans; Candidiasis, Vulvovaginal; Recurrence; Antifungal Agents
PubMed: 37948448
DOI: 10.1371/journal.ppat.1011684 -
BMC Infectious Diseases Aug 2023Candida auris is an emerging yeast pathogen that can cause invasive infections, particularly candidemia, in healthcare settings. Candida auris is characterized by...
BACKGROUND
Candida auris is an emerging yeast pathogen that can cause invasive infections, particularly candidemia, in healthcare settings. Candida auris is characterized by resistance to multiple classes of antifungal drugs and high mortality.
OBJECTIVE
To describe the risk factors, clinical characteristics, antifungal susceptibility pattern and outcomes of Candida auris blood stream infection.
METHODS
We conducted a retrospective review of electronic medical records of C. auris fungemia cases in the facilities under Hamad Medical corporation, Qatar from 1/11/2018 to 31/7/2021. Demographic data, risk factors, antibiogram and 30-day outcome are described.
RESULTS
We identified 36 patients with C. auris fungemia. Most of the patients were in intensive care unit following severe COVID-19 pneumonia and had received steroids and broad-spectrum antibiotics. Most cases were central line related. Over 90% of isolates were non-susceptible to fluconazole, while amphotericin B resistance reached 85%. Factors associated with high mortality included initial SOFA score of 9 or above and absence of source control.
CONCLUSION
Our study reveals a concerning 41.6% mortality rate within 30 days of C. auris candidemia. Furthermore, the prevalence of amphotericin B resistance in Qatar exceeds what has been reported in the literature necessitating further exploration. Echinocandins retains nearly 100% susceptibility and should be prioritized as the treatment of choice. These findings emphasize the need for vigilant monitoring and appropriate management strategies to combat C. auris infections and improve patient outcomes.
Topics: Humans; Amphotericin B; Antifungal Agents; Candida auris; Candidemia; COVID-19; Microbial Sensitivity Tests; Qatar
PubMed: 37544995
DOI: 10.1186/s12879-023-08477-5 -
Journal of Microbiology, Immunology,... Aug 2023The incidence of COVID-19-associated candidiasis (CAC) is increasing, resulting in a grave outcome among hospitalized patients with COVID-19. The most alarming condition... (Review)
Review
The incidence of COVID-19-associated candidiasis (CAC) is increasing, resulting in a grave outcome among hospitalized patients with COVID-19. The most alarming condition is the increasing incidence of multi-drug resistant Candida auris infections among patients with COVID-19 worldwide. The therapeutic strategy towards CAC caused by common Candida species, such as Candida albicans, Candida tropicalis, and Candida glabrata, is similar to the pre-pandemic era. For non-critically ill patients or those with a low risk of azole resistance, fluconazole remains the drug of choice for candidemia. For critically ill patients, those with a history of recent azole exposure or with a high risk of fluconazole resistance, echinocandins are recommended as the first-line therapy. Several novel therapeutic agents alone or in combination with traditional antifungal agents for candidiasis are potential options in the future. However, for multidrug-resistant C. auris infection, only echinocandins are effective. Infection prevention and control policies, including strict isolation of the patients carrying C. auris and regular screening of non-affected patients, are suggested to prevent the spread of C. auris among patients with COVID-19. Whole-genome sequencing may be used to understand the epidemiology of healthcare-associated candidiasis and to better control and prevent these infections.
Topics: Humans; Fluconazole; Candida auris; COVID-19; Antifungal Agents; Candidiasis, Invasive; Echinocandins; Azoles; Microbial Sensitivity Tests
PubMed: 36543722
DOI: 10.1016/j.jmii.2022.12.002 -
MBio Aug 2023The fungal pathogen represents a severe threat to hospitalized patients. Its resistance to multiple classes of antifungal drugs and ability to spread and resist...
The fungal pathogen 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 and narrowed our focus to five Food and Drug Administration (FDA)-approved compounds with inhibitory concentrations under 10 µM for 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 . To pursue these compounds further, we exposed to clioquinol in an extended experimental evolution study and found that 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 (causing upregulation of the drug transporter ) and in the drug transporter . These mutations had only modest effects on resistance to traditional antifungal agents, and the mutation rendered more susceptible to posaconazole. This observation raises the possibility that a combination treatment involving an 8-hydroxyquinoline and posaconazole might prevent from developing resistance to this established antifungal agent. IMPORTANCE The rapidly emerging fungal pathogen 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 . Although this compound has been identified in previous screens, we extended the analysis by showing that 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 and other fungal pathogens. Lohse and colleagues characterize a class of compounds that inhibit the fungal pathogen . Unlike many other antifungal drugs, does not readily develop resistance to this class of compounds.
Topics: Humans; Antifungal Agents; Candida auris; Candida; Clioquinol; Membrane Transport Proteins; Microbial Sensitivity Tests; Drug Resistance, Fungal
PubMed: 37493629
DOI: 10.1128/mbio.01376-23 -
Nature Communications Sep 2023The longstanding model is that most bloodstream infections (BSIs) are caused by a single organism. We perform whole genome sequencing of five-to-ten strains from blood...
The longstanding model is that most bloodstream infections (BSIs) are caused by a single organism. We perform whole genome sequencing of five-to-ten strains from blood culture (BC) bottles in each of ten patients with Candida glabrata BSI. We demonstrate that BCs contain mixed populations of clonal but genetically diverse strains. Genetically distinct strains from two patients exhibit phenotypes that are potentially important during BSIs, including differences in susceptibility to antifungal agents and phagocytosis. In both patients, the clinical microbiology lab recovered a fluconazole-susceptible index strain, but we identify mixed fluconazole-susceptible and -resistant populations. Diversity in drug susceptibility is likely clinically relevant, as fluconazole-resistant strains were subsequently recovered by the clinical laboratory during persistent or relapsing infections. In one patient, unrecognized respiration-deficient small colony variants are fluconazole-resistant and significantly attenuated for virulence during murine candidiasis. Our data suggest a population-based model of C. glabrata genotypic and phenotypic diversity during BSIs.
Topics: Humans; Animals; Mice; Antifungal Agents; Candida glabrata; Fluconazole; Blood Culture; Genotype; Sepsis
PubMed: 37739935
DOI: 10.1038/s41467-023-41509-x -
Annual Review of Microbiology Sep 2023Fungal-mediated disease progression and antifungal drug efficacy are significantly impacted by the dynamic infection microenvironment. At the site of infection, oxygen... (Review)
Review
Fungal-mediated disease progression and antifungal drug efficacy are significantly impacted by the dynamic infection microenvironment. At the site of infection, oxygen often becomes limiting and induces a hypoxia response in both the fungal pathogen and host cells. The fungal hypoxia response impacts several important aspects of fungal biology that contribute to pathogenesis, virulence, antifungal drug susceptibility, and ultimately infection outcomes. In this review, we summarize recent advances in understanding the molecular mechanisms of the hypoxia response in the most common human fungal pathogens, discuss potential therapeutic opportunities, and highlight important areas for future research.
Topics: Humans; Antifungal Agents; Hypoxia; Virulence; Disease Progression
PubMed: 37713457
DOI: 10.1146/annurev-micro-032521-021745 -
Revista Espanola de Quimioterapia :... Nov 2023New antifungal agents are needed to overcome limitations of available ones such as poor pharmacokinetic traits, toxicity, drug-drug interactions, limited clinical... (Review)
Review
New antifungal agents are needed to overcome limitations of available ones such as poor pharmacokinetic traits, toxicity, drug-drug interactions, limited clinical efficacy, and emerging antifungal resistance. New antifungal drugs belong to well-known families (azoles, polyenes, or beta-d-glucan synthase inhibitors) or to drug families showing completely new mechanisms of action. Some drugs have a head start in terms of potential to reach the clinical setting and are here reviewed.
Topics: Humans; Antifungal Agents; Mycoses; Azoles; Drug Resistance, Fungal; Polyenes
PubMed: 37997874
DOI: 10.37201/req/s01.14.2023