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《Saudi Pharmaceutical Journal》2023,31(9):101733
Human pathogenic fungi are responsible for causing a range of infection types including mucosal, skin, and invasive infections. Life-threatening and invasive fungal infections (FIs) are responsible for mortality and morbidity, especially for individuals with compromised immune function. The number of currently available therapeutic agents against invasive FIs is limited compared to that against bacterial infections. In addition, the increased mortality and morbidity caused by FIs are linked to the limited number of available antifungal agents, antifungal resistance, and the increased toxicity of these agents. Currently available antifungal agents have several drawbacks in efficiency, efficacy, toxicity, activity spectrum, and selectivity. It has already been demonstrated with numerous metallic nanoparticles (MNPs) that these nanoparticles can serve as an effective and alternative solution as fungicidal agents. MNPs have great potential owing to their intrinsic antifungal properties and potential to deliver antifungal drugs. For instance, gold nanoparticles (AuNPs) have the capacity to disturb mitochondrial calcium homeostasis induced AuNP-mediated cell death in Candida albicans. In addition, both copper nanoparticles and copper oxide nanoparticles exerted significant suppressive properties against pathogenic fungi. Silver nanoparticles showed strong antifungal properties against numerous pathogenic fungi, such as Stachybotrys chartarum, Mortierella alpina, Chaetomium globosum, A. fumigatus, Cladosporium cladosporioides, Penicillium brevicompactum, Trichophyton rubrum, C. tropicalis, and C. albicans. Iron oxide nanoparticles showed potent antifungal activities against A. niger and P. chrysogenum. It has also been reported that zinc oxide nanoparticles can significantly inhibit fungal growth. These NPs have already exerted potent antifungal properties against a number of pathogenic fungal species including Candida, Aspergillus, Fusarium, and many others. Several strategies are currently used for the research and development of antifungal NPs including chemical modification of NPs and combination with the available drugs. This review has comprehensively presented the current and innovative antifungal approach using MNPs. Moreover, different types of MNPs, their physicochemical characteristics, and production techniques have been summarized in this review. 相似文献
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《Expert opinion on drug discovery》2013,8(9):1117-1126
Introduction: Targeting pathogenetic mechanisms, rather than essential processes, represents a very attractive alternative for the development of new antibiotics. This may be particularly important in the case of antimycotics, due to the urgent need for novel antifungal drugs and the paucity of selective fungal targets. The opportunistic pathogenic fungus Candida albicans is the main etiological agent of candidiasis, the most common human fungal infection. These infections carry unacceptably high mortality rates, a clear reflection of the many shortcomings of current antifungal therapy, including the limited armamentarium of antifungal agents, their toxicity and the emergence of resistance. Moreover, the antifungal pipeline is mostly dry. Areas covered: This review covers some of the most recent progress toward understanding C. albicans pathogenetic processes and how to harness this information for the development of anti-virulence agents. The two principal areas covered are filamentation and biofilm formation, as C. albicans pathogenicity is intimately linked to its ability to undergo morphogenetic conversions between yeast and filamentous morphologies and to its ability to form biofilms. Expert opinion: Filamentation and biofilm formation represent high value targets, yet are clinically unexploited, for the development of novel anti-virulence approaches against candidiasis. Although this has proved a difficult task despite increasing understanding at the molecular level of C. albicans virulence, there are some opportunities and prospects for antifungal drug development targeting these two important biological processes. 相似文献
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《Expert opinion on emerging drugs》2013,18(2):231-250
The echinocandins are a new class of antifungals, developed in response to the need for safe and effective antifungals for the treatment of invasive fungal infections. These agents work by inhibiting 1,3-β-d-glucan synthase, an enzyme essential for production of cell walls in select fungi. Echinocandins appear to demonstrate favourable activity in vitro against a variety of yeasts (including both Candida albicans and non-albicans Candida) as well as select moulds (including Aspergillus spp.) In general, all echninocandins demonstrate a favourable safety profile and require once-daily parenteral administration. Caspofungin is the first of these agents to be available in the US, and is approved for empirical antifungal therapy in febrile neutropenic patients, candidaemia and select forms of invasive candidiasis, and for management of invasive aspergillosis in patients refractory to or intolerant of other therapies. Micafungin was recently approved by the FDA for treatment of oesophageal candidiasis, and for the prophylaxis of fungal infections in haematopoietic stem cell transplant recipients. Emerging data indicate micafungin may have an important role in the treatment of invasive forms of candidiasis. Anidulafungin is an echinocandin approved in the US for treatment of candidaemia and oesophageal candidiasis. Aminocandin (HMR-3702, IP-960) is an investigational agent, with published experience limited to in vitro studies and animal models of infection. 相似文献
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《International journal of antimicrobial agents》2014,43(5):395-402
The past decades have witnessed a dramatic increase in invasive fungal infections, especially candidiasis. Despite the development of more effective new antifungal agents, fluconazole (FLC) is still widely used in the clinic because of its efficacy and low toxicity. However, as the number of patients treated with FLC has increased, FLC-resistant Candida albicans isolates emerge more frequently. In addition, biofilm-associated infections are commonly encountered and their resistance poses a great challenge to antifungal treatment. Various approaches have been proposed to increase the susceptibility of C. albicans to FLC in order to cope with treatment failures, among which is the combination of FLC with different classes of non-antifungal agents such as antibacterials, calcineurin inhibitors, heat shock protein 90 inhibitors, calcium homeostasis regulators and traditional Chinese medicine drugs. Interestingly, many of these combinations showed synergistic effects against C. albicans, especially resistant strains. The main mechanisms of these synergistic effects appear to be increasing the permeability of the membrane, reducing the efflux of antifungal drugs, interfering with intracellular ion homeostasis, inhibiting the activity of proteins and enzymes required for fungal survival, and inhibiting biofilm formation. These modes of action and the antifungal mechanisms of various compounds referenced in this paper highlight the idea that the reversal of fungal resistance can be achieved through various mechanisms. Studies examining drug interactions will hopefully provide new approaches against antifungal drug resistance as well as insight into antifungal agent discovery. 相似文献
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Giulio Cesare Porretta Rossella Fioravanti Mariangela Biava Marino Artico Adelaide Villa Nicola Simonetti 《Archiv der Pharmazie》1995,328(9):667-672
A series of naftifine analogues having the biphenyl instead of the naphthyl moiety have been synthesized in a search devoted to study bioanalogues of clinically efficacious antifungal agents. The new derivatives were tested against Candida albicans by the direct contact method. They were also assayed against Gram-positive and Gram-negative bacteria and against some isolates of plant pathogenic fungi. Derivatives 8a, 8c , and 9a were found to be active against Candida albicans, derivative 5a was active against E. coli, a very resistant species to antimycotic agents, and derivatives 8a and 8b inhibited the plant pathogenic Rhizoctonia solani. 相似文献
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Abstract: Previous studies have shown that peptides derived from the N‐terminal region of the low molecular mass human salivary mucin, MUC7, possess potent in vitro cidal activity against Candida albicans and other medically important fungi. MUC7 12‐mer (residues 40–51 of the parent MUC7) peptide, having the optimal size and a net charge of +6, was found to be anticandidal in human saliva (clarified and unclarified), and its candidacidal potency was found to be superior to that of histatin 5 12‐mer (Hsn5 12‐mer). We have, therefore, explored the candidacidal potency of MUC7 12‐mer (l and d isomers) and Hsn5 12‐mer peptides in vivo. In vitro killing assay was performed to establish killing activity of the peptides against C. albicans prior to in vivo experiments. A murine model of oral candidiasis that has the characteristics of oral thrush in humans was employed for the in vivo studies, based on a previous protocol. Upon candidal induction, antifungal treatment application using agents emulsified in Pluronic F127 was performed for six consecutive days. Amphotericin B and clotrimazole emulsified in the same delivery system were used as positive control drugs. Candidacidal efficacy was evaluated microbiologically and histopathologically. Results demonstrated a considerable reduction of fungal burden by the MUC7 12‐mer peptides (l and d ), comparable to control drugs, and this effect was statistically significant, unlike the effect seen with Hsn5 12‐mer. Murine oral candidiasis model employed in this study is suitable to test the candidacidal agents employing Pluronic F127. In conclusion, MUC7 12‐mer appears to be a promising candidate as an antifungal agent for oral candidiasis. 相似文献
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Monali Gajbhiye Jayendra Kesharwani Avinash Ingle Aniket Gade Mahendra Rai 《Nanomedicine : nanotechnology, biology, and medicine》2009,5(4):382-386
Silver nanoparticles (Ag-NPs) are known to have inhibitory and bactericidal effects. Resistance of fungal infections has emerged in recent years and is a major health problem. Here, we report the extracellular biosynthesis of Ag-NPs using a common fungus, Alternaria alternata. Also in this study, these nanoparticles were evaluated for their part in increasing the antifungal activity of fluconazole against Phoma glomerata, Phoma herbarum, Fusarium semitectum, Trichoderma sp., and Candida albicans. The antifungal activity of fluconazole was enhanced against the test fungi in the presence of Ag-NPs. Fluconazole in combination with Ag-NPs showed the maximum inhibition against C. albicans, which was confirmed from the increase in fold area of inhibition, followed by P. glomerata and Trichoderma sp., which showed less increase in the fold area, whereas no significant enhancement of activity was found against P. herbarum and F. semitectum.From the Clinical EditorThe antifungal activity of fluconazole was enhanced in presence of silver nanoparticles against the test fungi. Fluconazole in combination with Ag-NPs showed the maximum inhibition against C. albicans, followed by P. glomerata and Trichoderma sp. No significant enhancement of activity was found against P. herbarum and F. semitectum. 相似文献
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Matthew C. Stensberg Rajtarun Madangopal Gowri Yale Qingshan Wei Hugo Ochoa-Acuña Alexander Wei 《Nanotoxicology》2014,8(8):833-842
Silver nanoparticles (Ag NPs) are gaining popularity as bactericidal agents in commercial products; however, the mechanisms of toxicity (MOT) of Ag NPs to other organisms are not fully understood. It is the goal of this research to determine differences in MOT induced by ionic Ag+ and Ag NPs in Daphnia magna, by incorporating a battery of traditional and novel methods. Daphnia embryos were exposed to sublethal concentrations of AgNO3 and Ag NPs (130–650 ng/L), with uptake of the latter confirmed by confocal reflectance microscopy. Mitochondrial function was non-invasively monitored by measuring proton flux using self-referencing microsensors. Proton flux measurements revealed that while both forms of silver significantly affected proton efflux, the change induced by Ag NPs was greater than that of Ag+. This could be correlated with the effects of Ag NPs on mitochondrial dysfunction, as determined by confocal fluorescence microscopy and JC-1, an indicator of mitochondrial permeability. However, Ag+ was more efficient than Ag NPs at displacing Na+ within embryonic Daphnia, based on inductively coupled plasma-mass spectroscopy (ICP-MS) analysis. The abnormalities in mitochondrial activity for Ag NP-exposed organisms suggest a nanoparticle-specific MOT, distinct from that induced by Ag ions. We propose that the MOT of each form of silver are complementary, and can act in synergy to produce a greater toxic response overall. 相似文献
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《Expert opinion on pharmacotherapy》2013,14(12):2037-2048
Importance of the field: Candida species are the fourth leading cause of nosocomial bloodstream infections in the United States. They are a leading cause of invasive fungal infections and are an emerging problem in hospital medicine.Areas covered in this review: The antifungal armamentarium for the treatment of systemic fungal infections has increased in recent years and now comprises agents from four main drug classes. This article summarizes the role of antifungal agents in the treatment of infections due to Candida albicans (C. albicans).What the reader will gain: An extensive summary of currently available antifungal agents active against C. albicans. Clinical trials involving these agents will be discussed. Areas covered include drug pharmacokinetics, mechanisms of action, and toxicities.Take home message: New antifungal agents have contributed to significant advances in the treatment of C. albicans. A detailed knowledge of differences in spectrum of activity, toxicity profiles, bioavailability, formulations, and drug interactions of these agents is required. Despite these recent advances, the attributable mortality rates of candidemia and invasive candidiasis remain very high, reminding us of the importance of strategies for the prevention of these infections. 相似文献
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根据氮唑类抗真菌化合物的构效关系和作用机理,设计合成了29个1-{2-[(4-取代苯基)甲氧基]-2-(取代苯基)乙基}-1H-氮唑类化合物,其中九个为首次报道。初步体外抑菌试验结果表明,大多数目标化合物对八种试验菌株都有不同程度的抗真菌活性。化合物14对白念珠菌的活性与克霉唑及益康唑相当,对其它七种试验菌株的活性明显强于克霉唑及益康唑。化合物4,12对白念珠菌活性差,对其它七种试验菌株的活性也强于克霉唑和益康唑。化合物5,6和23除对白念珠菌外,对其它七种试验菌株,也有较强活性。 相似文献
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目的 了解2014—2017年解放军总医院海南分院真菌的分布和耐药特点,为促进抗真菌药的合理应用、有效减缓真菌耐药提供参考。方法 提取解放军总医院海南分院2014年1月—2017年12月临床真菌分离和药敏相关数据,分析真菌的分布特征及其对常用抗真菌药的耐药率和变化趋势。结果 共纳入1 048份阳性真菌样本,呼吸道标本占41.89%,60岁以上患者(61.45%)和重症医学科(25.48%)分布比例最高;共分离出1 329株真菌,白色念珠菌、念珠菌属、热带念珠菌分别占24.53%、15.80%、13.69%。各种念珠菌对两性霉素B和5-氟胞嘧啶的敏感率基本保持在90%以上;热带念珠菌对伊曲康唑耐药率最高,达10%~20%,对氟康唑和伏立康唑的耐药率亦高于两性霉素B和5-氟胞嘧啶;白色念珠菌对伊曲康唑和伏立康唑的耐药率呈逐年快速上升趋势。结论 白色念珠菌和热带念珠菌感染应慎用唑类抗真菌药;两性霉素B和5-氟胞嘧啶是念珠菌感染的有效选择。 相似文献
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《Current medical research and opinion》2013,29(7):1761-1768
AbstractSeriously ill or immunocompromised children are at increased risk of invasive fungal infections, particularly candidemia. Candida albicans and Candida parapsilosis are the two most frequent causes of candidemia in pediatric patients. Candidemia in children is associated with high morbidity and mortality, increased length of hospital stays, and higher healthcare costs. Early effective antifungal therapy is the key to improved outcomes. Risk factors for candidemia may be used to identify patients suitable for empiric therapy. Such risk factors include prolonged stay in an intensive care unit, immunosuppression, prior bacterial infection, and recent surgery, as well as the use of a central venous catheter, mechanical ventilation, and/or total parenteral nutrition. Recent guidelines from the Infectious Diseases Society of America recommend consideration of fluconazole or an echinocandin for empiric therapy in suitable candidates, with a preference for an echinocandin in patients with moderate-to-severe disease, recent azole exposure, or high risk of Candida glabrata or Candida krusei infection. Fluconazole or an echinocandin is also preferred initial therapy for non-neutropenic candidemia, depending on disease severity and other characteristics. The guidelines recommend treatment with an echinocandin or lipid formulation of amphotericin B for most patients with neutropenic candidemia, although fluconazole is identified as an alternative for less critically ill patients without recent azole exposure. Risk factors for candidemia – and, hence, criteria for prophylaxis – are less well established in older children than in neonates. Further research is needed to better establish criteria for antifungal prophylaxis in children at high risk for candidemia. 相似文献
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《Expert opinion on therapeutic patents》2013,23(8):771-786
The search for new and effective antifungal agents has been intensified by the increase in the incidence of opportunistic infections due to immunological diseases and aggressive immunosuppressive chemotherapy. Natural products have provided several novel leads in this field. Of these the echinocandin lipopeptides are of special interest due to their fungicidal properties and low toxicity. Their mode of action uniquely targets fungal cell wall biosynthesis by inhibiting the production of β-(1,3)-D-glucan, an essential cell wall component. Echinocandin B (ECB) consists of a cyclic hexapeptide whose N-terminus is acylated with linoleic acid. Other natural products of this class have closely related structures with some modification of the cyclic peptide and/or the N-acyl fatty acid chain. Although these natural products share excellent antifungal activity, especially against Candida albicans, and low toxicity, further improvements in therapeutic and solubility properties were sought through chemical modification. Major efforts have been ongoing at both Merck and Lilly in the quest for natural and semisynthetic echinocandin lipopeptides which will provide novel clinical candidates with a unique mode of action. This article describes the development of this class of compounds by reviewing both the primary and patent literature. 相似文献
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《Nanotoxicology》2013,7(4):527-542
AbstractToxic effects of silver nanoparticles (Ag NPs) are, in most cases, measured within a single generation, while information regarding multigenerational exposure remains scarce. The current study assessed changes in toxic response (reproduction, fertility, and development) towards Ag NPs (NM300K; uncoated, 16.7?±?6.5?nm) compared to AgNO3 over six generations, following chronic exposure of the model organism Caenorhabditis elegans. This revealed that AgNO3 exposure was associated with no changes in susceptibility to Ag. In contrast, multigenerational exposure to sub-lethal concentrations of Ag NPs resulted in persistent delayed development, but rendered increased tolerance to Ag NP with respect to fertility and fecundity. The results thus permit inference of a difference in toxic mode of action of the two forms of Ag, which instigate different response patterns. Results reveal a novel mechanism for the adaptation toward Ag NPs, where increased reproductive fitness occurs at the expense of somatic growth. This adaptive mechanism was, however associated with increased susceptibility to AgNO3 with respect to growth, fertility and reproduction. The current study thus demonstrates that a nano-specific resistance can be developed by C. elegans. Importantly, this adaptation renders increased vulnerability to another environmental stressor, and thus exposure to a second contaminant could be detrimental to such populations. 相似文献
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Amphotericin B (AMB) is used most commonly in severe systemic life-threatening fungal infections. There is currently an unmet need for an efficacious (AMB) formulation amenable to oral administration with better bioavailability and lower nephrotoxicity. Novel PEGylated polylactic-polyglycolic acid copolymer (PLGA-PEG) nanoparticles (NPs) formulations of AMB were therefore studied for their ability to kill Candida albicans (C. albicans). The antifungal activity of AMB formulations was assessed in C. albicans. Its bioavalability was investigated in nine groups of rats (n?=?6). Toxicity was examined by an in vitro blood hemolysis assay, and in vivo nephrotoxicity after single and multiple dosing for a week by blood urea nitrogen (BUN) and plasma creatinine (PCr) measurements. The MIC of AMB loaded to PLGA-PEG NPs against C. albicans was reduced two to threefold compared with free AMB. Novel oral AMB delivery loaded to PLGA-PEG NPs was markedly systemically available compared to Fungizone® in rats. The addition of 2% of GA to the AMB formulation significantly (p?0.05) improved the bioavailability from 1.5 to 10.5% and the relative bioavailability was?>?790% that of Fungizone®. The novel AMB formulations showed minimal toxicity and better efficacy compared to Fungizone®. No nephrotoxicity in rats was detected after a week of multiple dosing of AMB NPs based on BUN and PCr, which remained at normal levels. An oral delivery system of AMB-loaded to PLGA-PEG NPs with better efficacy and minimal toxicity was formulated. The addition of glycyrrhizic acid (GA) to AMB NPs formulation resulted in a significant oral absorption and improved bioavailability in rats. 相似文献