Systemic fungal infections pose a serious clinical problem. Treatment options are limited, and antifungal drug resistance is increasing. In addition, a substantial proportion of patients do not ...respond to therapy despite being infected with fungi that are susceptible to the drug. The discordance between overall treatment outcome and low levels of clinical resistance may be attributable to antifungal drug tolerance. In this Review, we define and distinguish resistance and tolerance and discuss the current understanding of the molecular, genetic and physiological mechanisms that contribute to those phenomena. Distinguishing tolerance from resistance might provide important insights into the reasons for treatment failure in some settings.
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FZAB, GEOZS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Candida albicans is frequently detected with heavy infection by Streptococcus mutans in plaque-biofilms from children with early-childhood caries (ECC). This cross-kingdom biofilm contains an ...extensive matrix of extracellular α-glucans that is produced by an exoenzyme (GtfB) secreted by S. mutans. Here, we report that mannans located on the outer surface of C. albicans cell-wall mediates GtfB binding, enhancing glucan-matrix production and modulating bacterial-fungal association within biofilms formed in vivo. Using single-molecule atomic force microscopy, we determined that GtfB binds with remarkable affinity to mannans and to the C. albicans surface, forming a highly stable and strong bond (1-2 nN). However, GtfB binding properties to C. albicans was compromised in strains defective in O-mannan (pmt4ΔΔ) or N-mannan outer chain (och1ΔΔ). In particular, the binding strength of GtfB on och1ΔΔ strain was severely disrupted (>3-fold reduction vs. parental strain). In turn, the GtfB amount on the fungal surface was significantly reduced, and the ability of C. albicans mutant strains to develop mixed-species biofilms with S. mutans was impaired. This phenotype was independent of hyphae or established fungal-biofilm regulators (EFG1, BCR1). Notably, the mechanical stability of the defective biofilms was weakened, resulting in near complete biomass removal by shear forces. In addition, these in vitro findings were confirmed in vivo using a rodent biofilm model. Specifically, we observed that C. albicans och1ΔΔ was unable to form cross-kingdom biofilms on the tooth surface of rats co-infected with S. mutans. Likewise, co-infection with S. mutans defective in GtfB was also incapable of forming mixed-species biofilms. Taken together, the data support a mechanism whereby S. mutans-secreted GtfB binds to the mannan layer of C. albicans to promote extracellular matrix formation and their co-existence within biofilms. Enhanced understanding of GtfB-Candida interactions may provide new perspectives for devising effective therapies to disrupt this cross-kingdom relationship associated with an important childhood oral disease.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
...our laboratory used the AK assay in a screen of mechanistically distinct protein kinase inhibitors designed to identify fungilytic inhibitors of the cell wall integrity kinase signaling cascade, a ...stress response pathway conserved across pathogenic fungi. Perspective An interesting theme shared by the new antifungal targets described above is that many target proteins with orthologs in human cells. Since the targets of most current antifungal drugs are unique to fungi, this represents a significant conceptual evolution that seeks to exploit the sometimes subtle differences in protein structure between host and pathogen to identify molecules with selectivity for the fungal protein and, thereby, acceptable toxicity toward the host.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
...these mannoprotein-deficient mutants developed poor mixed-species biofilms with S. mutans, showed reduced EPS α-glucans content, and reduced microbial carriage on teeth in vivo 18. ...the ...organisms enhance the carriage of cariogenic pathogens, biofilm accumulation, and acid production, promoting a localized and persistent acidogenic–aciduric microenvironment that potentiates demineralization of tooth enamel and may explain the synergistic enhancement of caries severity. Paradoxically, farnesol produced by C. albicans, which stimulates S. mutans growth and gtfB expression at low concentrations (25–50 μM), disrupts bacterial growth at high concentrations (>100 μM) 27. ...a tightly regulated cooperative and antagonistic balance through stimulus-inhibition mechanisms appears to mediate bacterial–fungal coexistence and survival within biofilms, which can become synergistic when conditions are conducive for disease (Fig 2). Elucidating how bacterial–fungal interactions occur spatiotemporally (cooperative, competitive, or both simultaneously) to mediate symbiotic, antagonistic, or synergistic states may shed new light into the pathogenic mechanisms and identify more effective therapeutic targets. Since cross-kingdom biofilms exist throughout the gastrointestinal tract, principles and molecules that emerge from these studies may lead to novel approaches to prevent and eradicate other intractable polymicrobial biofilms at various clinical niches.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Invasive, life-threatening fungal infections are an important cause of morbidity and mortality, particularly for patients with compromised immune function. The number of therapeutic options for the ...treatment of invasive fungal infections is quite limited when compared with those available to treat bacterial infections. Indeed, only three classes of molecules are currently used in clinical practice and only one new class of antifungal drugs has been developed in the last 30 years. Here we summarize the unmet clinical needs of current antifungal therapy, discuss challenges inherent to antifungal drug discovery and development, and review recent developments aimed at addressing some of these challenges.
C. albicans transitions between budding yeast and filamentous hyphal forms in a process that is tightly associated with its virulence. This transition also occurs after the fungus has been ...phagocytosed by macrophages. A number of somewhat discordant models have been proposed for the environmental characteristics of the phagolysosome that induce this transition. H. B. Wilson and M. C. Lorenz (Infect Immun 91:e00087-23, 2023, https://doi.org/10.1128/iai.00087-23) revisited these models and found that none of them explained morphogenesis in the macrophage.
•Review of the current state of anti-cryptococcal therapy.•Proposal for ideal anti-cryptococcal therapy.•Review of recent progress toward new therapies.
Cryptococcosis is one of the most important ...fungal infections of humans. It primarily, but not exclusively, afflicts people with compromised immune function. Cryptococcosis is most commonly caused by Cryptococcus neoformans var. grubii with C. neoformans var. neoformans and C. gatti also contributing to the disease. Cryptococcosis is primarily manifested as meningoencephalitis although pneumonia occurs frequently as well. Globally, the burden of disease is highest among those living with HIV/AIDS and is one of the most common causes of death in this patient population. Cryptococcal meningitisis almost invariably fatal if untreated. The current gold standard therapy is amphotericin B combined with 5-flucytosine. Unfortunately, this therapy has significant toxicity and is not widely available in resource-limited regions. Fluconazole, which is associated with poorer outcomes, is frequently as an alternative. Here, I present the characteristics of an ideal anti-cryptococcal agent and review recent progress toward identifying both novel and repurposed drugs as potential new therapies.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
How Do C. albicans Filaments Kill Macrophages? Because of the visual/temporal association of intracellular filament growth with macrophage lysis, a logically appealing hypothesis is that C. ...albicans filaments simply grow so long that the macrophage membrane is stretched to the point of failure, resulting in lysis 2, 5. ...C. albicans mutant strains that do not form filaments also do not trigger macrophage lysis 10.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The concept of repurposing previously approved medications to the treatment of new indications by taking advantage of off-target effects has gained traction in recent years, particularly in areas of ...medicine that do not offer large profits to pharmaceutical firms. As infectious disease discovery research has declined among large pharmaceutical companies, the potential payoff of repurposing has become attractive. From these efforts, the triphenylethylene class of selective estrogen receptor modulators related to tamoxifen has shown activity against a wide range of medically important human pathogens, including bacteria, fungi, parasites, and viruses. Because it has activity against many pathogens affecting people in resource-limited areas of the world, TAM and related drugs may be particularly useful. Here, we review the
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, and mechanistic studies of the anti-infective activity of tamoxifen, toremifene, clomiphene, and their analogs. We also discuss the pharmacologic properties of this privileged scaffold and its potential utility in treating infectious diseases.
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