Drug-resistant Fungal Infections Research Articles

Plain language summary: Does a person's age affect how common fungal infections are and how well drugs can kill the infections?

Fungi are types of microbes that include molds and yeasts. Fungal infections can make people ill and can even cause death, especially in older people. They can be treated using antifungal drugs, but some fungi are drug resistant. This means the drug cannot kill the fungi. This is a summary based on a study that looked at fungal samples to find out more about antifungal drug resistance in adults younger than 65 compared with adults aged 65 and older. The study found that one type of drug-resistant fungus, called Candida parapsilosis, was more common in older people than in younger people. Another type, called Aspergillus fumigatus, was more common in younger people than in older people. We also found genetic changes in drug-resistant fungi. These changes could explain why the drugs did not work. We hope that the findings from this study can help scientists create new treatments for drug-resistant fungal infections.

An Effective Strategy to Develop Potent and Selective Antifungal Agents from Cell Penetrating Peptides in Tackling Drug-Resistant Invasive Fungal Infections.

The high mortality rate of invasive fungal infections and quick emergence of drug-resistant fungal pathogens urgently call for potent antifungal agents. Inspired by the cell penetrating peptide (CPP) octaarginine (R8), we elongated to 28 residues poly(d,l-homoarginine) to obtain potent toxicity against both fungi and mammalian cells. Further incorporation of glutamic acid residues shields positive charge density and introduces partial zwitterions in the obtained optimal peptide polymer that displays potent antifungal activity against drug-resistant fungi superior to antifungal drugs, excellent stability upon heating and UV exposure, negligible in vitro and in vivo toxicity, and strong therapeutic effects in treating invasive fungal infections. Moreover, the peptide polymer is insusceptible to antifungal resistance owing to the unique CPP-related antifungal mechanism of fungal membrane penetration followed by disruption of organelles within fungal cells. All these merits imply the effectiveness of our strategy to develop promising antifungal agents.

Synthesis, Antimicrobial Evaluation, and Molecular Modeling Studies of New Thiosemicarbazide-Triazole Hybrid Derivatives of (S)-Naproxen.

The discovery of new antimicrobial molecules is crucial for combating drug-resistant bacterial and fungal infections that pose a dangerous threat to human health. In the current research, we applied a molecular hybridization approach to synthesize original thiosemicarbazide-triazole derivatives starting from (S)-naproxen (7a-7k). After structural characterization using FT-IR, 1 H-NMR, 13 C-NMR, and HR-MS, the obtained compounds were screened for their antimicrobial activities against Staphylococcus aureus ATCC 29213, Escherichia coli ATCC 25922, Candida albicans ATCC 10231 and their isolates, as well. Although all compounds were found to be moderate antimicrobial agents, in general, their antibacterial activities were better than antifungal effects. Among the tested compounds, 7j carrying nitrophenyl group on the thiosemicarbazide functionality represented the best MIC value against S. aureus isolate. Finally, molecular docking studies were performed in the active pocket of S. aureus flavohemoglobin to rationalize the obtained biological data.

Short Guanidinium-Functionalized Poly(2-oxazoline)s Displaying Potent Therapeutic Efficacy on Drug-Resistant Fungal Infections.

New antifungals are urgently needed to combat invasive fungal infections, due to limited types of available antifungal drugs and frequently encountered side effects, as well as the quick emergence of drug-resistance. We previously developed amine-pendent poly(2-oxazoline)s (POXs) as synthetic mimics of host defense peptides (HDPs) to have antibacterial properties, but with poor antifungal activity. Hereby, we report the finding of short guanidinium-pendent POXs, inspired by cell-penetrating peptides, as synthetic mimics of HDPs to display potent antifungal activity, superior mammalian cells versus fungi selectivity, and strong therapeutic efficacy in treating local and systemic fungal infections. Moreover, the unique antifungal mechanism of fungal cell membrane penetration and organelle disruption explains the insusceptibility of POXs to antifungal resistance. The easy synthesis and structural diversity of POXs imply their potential as a class of promising antifungal agents.

Design, synthesis and evaluation of novel 5-phenylthiophene derivatives as potent fungicidal of Candida albicans and antifungal reagents of fluconazole-resistant fungi.

A series of 5-phenylthiophene derivatives with novel structures were designed and synthesized to combat the increasing incidence of susceptible and drug-resistant fungal infections. The antifungal activity of the synthesized compounds was assessed against seven susceptible strains and six fluconazole-resistant strains. It is especially encouraging that compounds 17b and 17f displayed significant antifungal activities against all tested strains. Furthermore, the potent compounds 17b and 17f could prevent the formation of fungi biofilms and 17f displayed satisfactory fungicidal activity. Preliminary mechanistic studies showed that the potent antifungal activity of compound 17f stemmed from inhibition of C.albicans CYP51. In addition, Compounds 17b and 17f were almost nontoxic to mammalian A549, MCF-7, and THLE-2cells. These results strongly suggested that compounds 17b and 17f are promising as novel antifungal drugs.

Alternative Treatment Strategies for Secondary Bacterial and Fungal Infections Associated with COVID-19.

Antimicrobials are essential for combating infectious diseases. However, an increase in resistance to them is a major cause of concern. The empirical use of drugs in managing COVID-19 and the associated secondary infections have further exacerbated the problem of antimicrobial resistance. Hence, the situation mandates exploring and developing efficient alternatives for the treatment of bacterial and fungal infections in patients suffering from COVID-19 or other viral infections. In this review, we have described the alternatives to conventional antimicrobials that have shown promising results and are at various stages of development. An acceleration of efforts to investigate their potential as therapeutics can provide more treatment options for clinical management of drug-resistant secondary bacterial and fungal infections in the current pandemic and similar potential outbreaks in the future. The alternatives include bacteriophages and their lytic enzymes, anti-fungal enzymes, antimicrobial peptides, nanoparticles and small molecule inhibitors among others. What is required at this stage is to critically examine the challenges in developing the listed compounds and biomolecules as therapeutics and to establish guidelines for their safe and effective application within a suitable time frame. In this review, we have attempted to highlight the importance of rational use of antimicrobials in patients suffering from COVID-19 and boost the deployment of alternative therapeutics.

Synergistic potential of essential oils with antibiotics to combat fungal pathogens: Present status and future perspectives.

The steady rise in the emergence of antibiotic-resistant fungal pathogens has rendered most of the clinical antibiotics available in the market to be ineffective. Therefore, alternative strategies are required to tackle drug-resistant fungal infections. An effective solution is to combine the available antibiotics with adjuvants such as phytochemicals or essential oils to enhance the efficacy and activity of antibiotics. The present review aims to summarize the studies on synergistic combinations of essential oils and anti-fungal antibiotics. The current findings, methods used for measuring synergistic effects, possible mechanisms of synergism, and future perspectives for developing synergistic EO-antibiotic therapeutic formulations are discussed in this study. Several essential oils exhibit synergistic effect in combination with antibiotics against human fungal pathogens such as Candida albicans. The possible mechanisms of synergy exhibited by essential oil- antibiotic combinations in fungi include disruption of cell wall structure/ ergosterol biosynthesis pathway, enhanced transdermal penetration of antibiotics, alterations in membrane permeability, intracellular leakage of cellular contents, inhibition of germ tube formation or fungal biofilm formation, and competition for a primary target. Synergistic combination of essential oils and antibiotics can prove to be a valid and pragmatic alternative to develop drugs with increased drug-efficacy, and low toxicity.

Fungal infections in transplant recipients: pros and cons of immunosuppressive and antimicrobial treatment

Fungal infections in transplant recipients: pros and cons of immunosuppressive and antimicrobial treatment

Nontoxic Cobalt(III) Schiff Base Complexes with Broad-Spectrum Antifungal Activity.

Resistance to currently available antifungal drugs has quietly been on the rise but overshadowed by the alarming spread of antibacterial resistance. There is a striking lack of attention to the threat of drug‐resistant fungal infections, with only a handful of new drugs currently in development. Given that metal complexes have proven to be useful new chemotypes in the fight against diseases such as cancer, malaria, and bacterial infections, it is reasonable to explore their possible utility in treating fungal infections. Herein we report a series of cobalt(III) Schiff base complexes with broad‐spectrum antifungal activity. Some of these complexes show minimum inhibitory concentrations (MIC) in the low micro‐ to nanomolar range against a series of Candida and Cryptococcus yeasts. Additionally, we demonstrate that these compounds show no cytotoxicity against both bacterial and human cells. Finally, we report the first in vivo toxicity data on these compounds in Galleria mellonella, showing that doses as high as 266 mg kg−1 are tolerated without adverse effects, paving the way for further in vivo studies of these complexes.

A Novel Dual-Targeted α-Helical Peptide With Potent Antifungal Activity Against Fluconazole-Resistant Candida albicans Clinical Isolates.

Due to compromised immune system, fungal infection incidences have markedly increased in the last few decades. Pathogenic fungi have developed resistance to the clinically available antifungal agents. Antifungal resistance poses a great challenge to clinical treatment and has stimulated the demand for novel antifungal agents. A promising alternative to the treatment of fungal diseases is the use of antimicrobial peptides (AMPs). However, the antifungal activities of AMPs have not been fully determined. Therefore, this study aimed at designing and screening α-helical peptides with potential antifungal activities. The effects of key physicochemical parameters on antifungal activities were also investigated. A series of lengthened and residue-substituted derivatives of the template peptide KV, a hexapeptide truncated from the α-helical region of porcine myeloid antimicrobial peptide-36, were designed and synthesized. Enhancement of hydrophobicity by introducing aromatic hydrophobic amino acids (tryptophan and phenylalanine) significantly increased the efficacies of the peptides against Candida albicans strains, including fluconazole-resistant isolates. Increased hydrophobicity also elevated the toxic properties of these peptides. RF3 with moderate hydrophobicity exhibited potent anticandidal activities (GM = 6.96 μM) and modest hemolytic activities (HC10 > 64 μM). Additionally, repeated exposure to a subinhibitory concentration of RF3 did not induce resistance development. The antifungal mechanisms of RF3 were due to membrane disruptions and induction of reactive oxygen species production. Such a dual-targeted mechanism was active against drug-resistant fungi. These results show the important role of hydrophobicity and provide new insights into designing and developing antifungal peptides. Meanwhile, the successful design of RF3 highlights the potential utility of AMPs in preventing the spread of drug-resistant fungal infections.

Mechanistic Insight Into the Antifungal Effects of a Fatty Acid Derivative Against Drug-Resistant Fungal Infections.

The prevalence of drug-resistant pathogenic fungi is a major global health challenge. There is an urgent need for novel drugs that can exert a potent antifungal activity and overcome resistance. Newly discovered anti-fungal properties of existing compounds can potentially offer a rapid solution to address this persistent threat. We rationalized that structures which disrupt the fungal cell membrane could address the above unmet need. As fatty acids underpin the formation and stability of cell membranes, we used computational simulations to evaluate the interactions between selected short chain fatty acids and a model cell membrane. Here, we report that caprylic acid could penetrate and perturb the membrane in silico. Based on the in silico findings, we identified a derivative of this fatty acid that disrupts fungal membranes as detected using steady-state fluorescence anisotropy. We show that this fatty acid derivative is potent against a variety of fungal pathogens like Candida and Trichophyton. We further demonstrated the ability of this fatty acid derivative to potentiate some azoles in vitro and enhance the efficacy of antifungal formulations in vivo. Our data suggests the emergence of a novel therapy for effective disease management and overcoming anti-fungal drug resistance.

Interactions between invasive fungi and symbiotic bacteria.

Infection rates and mortality associated with the invasive fungi Candida, Aspergillus, and Cryptococcus are increasing rapidly in prevalence. Meanwhile, screening pressure brought about by traditional antifungal drugs has induced an increase in drug resistance of invasive fungi, which creates a great challenge for the preservation of physical health. Development of new drugs and novel strategies are therefore important to meet these growing challenges. Recent studies have confirmed that the dynamic balance of microorganisms in the body is correlated with the occurrence of infectious diseases. This discovery of interactions between bacteria and fungi provides innovative insight for the treatment of invasive fungal infections. However, different invasive fungi and symbiotic bacteria interact with each other through various ways and targets, leading to different effects on their growth, morphology, and virulence. And the mechanism and implication of these interactions remains largely unknown. The present review aims to summarize the research progress into the interaction between invasive fungi and symbiotic bacteria with a focus on the anti-fungal mechanisms of symbiotic bacteria, providing a new strategy against drug-resistant fungal infections.

Aspartate semialdehyde dehydrogenase inhibition suppresses the growth of the pathogenic fungus Candida albicans.

Potent inhibitors of an essential microbial enzyme have been shown to be effective growth inhibitors of Candida albicans, a pathogenic fungus. C. albicans is the main cause of oropharyngeal candidiasis, and also causes invasive fungal infections, including systemic sepsis, leading to serious complications in immunocompromised patients. As the rates of drug-resistant fungal infections continue to rise novel antifungal treatments are desperately needed. The enzyme aspartate semialdehyde dehydrogenase (ASADH) is critical for the functioning of the aspartate biosynthetic pathway in microbes and plants. Because the aspartate pathway is absent in humans, ASADH has the potential to be a promising new target for antifungal research. Deleting the asd gene encoding for ASADH significantly decreases the survival of C. albicans, establishing this enzyme as essential for this organism. Previously developed ASADH inhibitors were tested against several strains of C. albicans to measure their possible therapeutic impact. The more potent inhibitors show a good correlation between enzyme inhibitor potency and fungal growth inhibition. Growth curves generated by incubating different C. albicans strains with varying enzyme inhibitor levels show significant slowing of fungal growth by these inhibitors against each of these strains, similar to the effect observed with a clinical antifungal drug. The most effective inhibitors also demonstrated relatively low cytotoxicity against a human epithelial cell line. Taken together, these results establish that the ASADH enzyme is a promising new target for further development as a novel antifungal treatment against C. albicans and related fungal species.

Combating fluconazole-resistant fungi with novel β-azole-phenylacetone derivatives

A series of β-azole-phenylacetone derivatives with novel structures were designed and synthesized to combat the increasing incidence of susceptible fungal infections and drug-resistant fungal infections. The antifungal activity of the synthesized compounds was assessed against five susceptible strains and five fluconazole-resistant strains. Antifungal activity tests showed that most of the compounds exhibited excellent antifungal activities against five pathogenic strains with MIC values in the range of 0.03–1 μg/mL. Compounds with R1 = 3-F substituted and 15o and 15ae exhibited moderate antifungal activities against fluconazole-resistant strains 17# and CaR with MIC values in the range of 1–8 μg/mL. Compounds with R1 = H or 2-F (such as 15a, 15o, 15p) displayed moderate to good antifungal activity against fluconazole-resistant strains 632, 901 and 904 with MIC values in the range of 0.125–4 μg/mL. Notably, 15o and 15ae exhibited antifungal activity against five susceptible strains and five fluconazole-resistant strains. Preliminary mechanistic studies showed that the potent antifungal activity of compound 15ae stemmed from inhibition of C. albicans CYP51. Compounds 15o, 15z and 15ae were nearly nontoxic to mammalian A549 cells.

Small-Molecule Host-Defense Peptide Mimetic Antibacterial and Antifungal Agents Activate Human and Mouse Mast Cells via Mas-Related GPCRs.

Host-defense peptides (HDPs) have an important therapeutic potential against microbial infections but their metabolic instability and cellular cytotoxicity have limited their utility. To overcome these limitations, we utilized five small-molecule, nonpeptide HDP mimetics (smHDPMs) and tested their effects on cytotoxicity, antimicrobial activity, and mast cell (MC) degranulation. None of the smHDPMs displayed cytotoxicity against mouse 3T3 fibroblasts or human transformed liver HepG2 cells. However, one compound had both antifungal and antibacterial activity. Surprisingly, all five compounds induced degranulation in a human MC line, LAD2, and this response was substantially reduced in Mas-related G protein-coupled receptor (GPCR)-X2 (MRGPRX2)-silenced cells. Furthermore, all five compounds induced degranulation in RBL-2H3 cells expressing MRGPRX2 but this response was abolished in cells expressing naturally occurring loss-of-function missense variants G165E (rs141744602) and D184H (rs372988289). Mrgprb2 is the likely mouse ortholog of human MRGPRX2, which is expressed in connective tissue MCs (CTMCs) such as cutaneous and peritoneal MCs (PMCs). All five smHDPMs induced degranulation in wild-type PMCs but not in cells derived from Mrgprb2−/− mice. These findings suggest that smHDPMs could serve as novel targets for the treatment of drug-resistant fungal and bacterial infections because of their ability to harness CTMCs’ host defense functions.

Design, synthesis and biological evaluation of amide-pyridine derivatives as novel dual-target (SE, CYP51) antifungal inhibitors.

Based on the analysis of the squalene cyclooxygenase (SE) and 14α-demethylase (CYP51) inhibitors pharmacophore feature and the dual-target active sites, a series of compounds with amide-pyridine scaffolds have been designed and synthesized to treat the increasing incidence of drug-resistant fungal infections. In vitro evaluation showed that these compounds have a certain degree of antifungal activity. The most potent compounds 11a, 11b with MIC values in the range of 0.125-2 μg/ml had a broad-spectrum antifungal activity and exhibited excellent inhibitory activity against drug-resistant pathogenic fungi. Preliminary mechanism studies revealed that the compound 11b might play an antifungal role by inhibiting the activity of SE and CYP51. Notably compounds did not show the genotoxicity through plasmid binding assay. Finally, this study of molecular docking, ADME/T prediction and the construction of 3D QSAR model were performed. These results can point out the direction for further optimization of the lead compound.

Resistance of concern in fungi

Antifungal drugs save lives by treating serious fungal infections, just as antibacterial drugs (antibiotics) are used to treat bacterial infections. This is especially a concern for patients with invasive infections like those caused by the fungus Candida, a yeast, or the mold Aspergillus, which can cause serious health problems, including death. There are indications that reports of antifungal resistance are increasing among common fungal species. Some species of fungi are naturally resistant to treatment with certain types of antifungal medications. Other species can develop resistance over time due to improper antifungal use—for example, dosages too low or treatment courses that are not long enough. Some studies have indicated that antibacterial medications may also contribute to antifungal resistance. This resistance could occur for a variety of reasons. For example, antibacterial drugs can reduce good and bad bacteria in the gut, which creates favourable conditions for Candida growth. It is not yet known if decreasing the use of all or certain antibiotics can reduce Candida infections, but appropriate use of antibacterial and antifungal medications is one of the most important factors in fighting drug resistance. More information is needed about the risk antifungal resistance poses on human health and how many people are sickened by drug-resistant fungal infections each year. CDC and its partners are working to better understand why and how antifungal resistance emerges and to increase awareness among medical and public health communities about these infections. Ultimately, we need to develop better methods to prevent and control drug-resistant fungal infections.

Novel imidazole derivatives as antifungal agents: Synthesis, biological evaluation, ADME prediction and molecular docking studies

A series of 2-(substituteddithiocarbamoyl)-N-[4-((1H-imidazol-1-yl)methyl)phenyl]acetamide derivatives was designed and synthesized to combat the increasing incidence of drug-resistant fungal infections. All synthesized compounds were characterized by IR, 1H-NMR, 13C-NMR, and HRMS spectra and elemental analyses. Antifungal activity tests were performed against four different fungal strains. Molecular docking studies were performed to investigate the mode of action towards the fungal lanosterol 14α-demethylase, a cytochrome P450-dependent enzyme. ADME studies were carried out and a connection between activities and physicochemical properties of the target compounds was determined. Most of the final compounds exhibited significant activity against Candida albicans and Candida krusei with MIC50 value 12.5 μg/mL. The results of in vitro anti-Candida activity, a docking study and ADME prediction revealed that the newly synthesized compounds have potential anti-Candida activity and evidenced the most active derivative, 5b (2-Pyrrolidinthiocarbonylthio-N-[4-((1H-imidazol-1-yl)methyl)phenyl]acetamide), which can be further optimized as a lead compound.

Discovery of diazahexa/hepta cyclic cage-like compounds with broad-spectrum antifungal activity against Candida and Cryptococcus species.

Invasive fungal infections caused by Candida and Cryptococcus species lead to life threating infections in immunocompromised individuals. Furthermore, increasing incidence of fungal strains resistant to FDA-approved antifungal drugs along with the paucity of antifungal drugs warrants novel drugs to treat invasive fungal infections. In this study, we investigated the antifungal activity of a novel series of diazahexa/hepta cyclic cage-like compounds. Results indicate that compounds with unsubstituted and o-methyl substitution on aryl rings exhibit potent broad-spectrum antifungal activity against various fungal strains. In addition, these compounds showed significant inhibitory activity against Candida hyphae and biofilm formation. Collectively, results from this study indicate that these compounds are promising candidates to develop as novel antifungal drugs to treat drug-resistant fungal infections.

Principles of Immunotherapy: Implications for Treatment Strategies in Cancer and Infectious Diseases.

The advances in cancer biology and pathogenesis during the past two decades, have resulted in immunotherapeutic strategies that have revolutionized the treatment of malignancies, from relatively non-selective toxic agents to specific, mechanism-based therapies. Despite extensive global efforts, infectious diseases remain a leading cause of morbidity and mortality worldwide, necessitating novel, innovative therapeutics that address the current challenges of increasing antimicrobial resistance. Similar to cancer pathogenesis, infectious pathogens successfully fashion a hospitable environment within the host and modulate host metabolic functions to support their nutritional requirements, while suppressing host defenses by altering regulatory mechanisms. These parallels, and the advances made in targeted therapy in cancer, may inform the rational development of therapeutic interventions for infectious diseases. Although “immunotherapy” is habitually associated with the treatment of cancer, this review accentuates the evolving role of key targeted immune interventions that are approved, as well as those in development, for various cancers and infectious diseases. The general features of adoptive therapies, those that enhance T cell effector function, and ligand-based therapies, that neutralize or eliminate diseased cells, are discussed in the context of specific diseases that, to date, lack appropriate remedial treatment; cancer, HIV, TB, and drug-resistant bacterial and fungal infections. The remarkable diversity and versatility that distinguishes immunotherapy is emphasized, consequently establishing this approach within the armory of curative therapeutics, applicable across the disease spectrum.