Candida is an intractable life-threatening pathogen. Candida infection is extremely difficult to eradicate, and thus is the major cause of morbidity and mortality in immunocompromised individuals. Morevover, the rapid spread of drug-resistant fungi has led to significant decreases in the therapeutic effects of clinical drugs. New anti-Candida agents are urgently needed to solve the complicated medical problem. Natural products with intricate structures have attracted great attention of researchers who make every endeavor to discover leading compounds for antifungal agents. Their novel mechanisms and diverse modes of action expand the variety of fungistatic agents and reduce the emergence of drug resistance. In recent decades, considerable effort has been devoted to finding unique antifungal agents from nature and revealing their unusual mechanisms, which results in important progress on the development of new antifungals, such as the novel cell wall inhibitors YW3548 and SCY-078 which are being tested in clinical trials. This review will present a brief summary on the landscape of anti-Candida natural products within the last decade. We will also discuss in-depth the research progress on diverse natural fungistatic agents along with their novel mechanisms.
Antifungal Agents/pharmacology* ; Biological Products/pharmacology* ; Candida/drug effects* ; Candidiasis/drug therapy* ; Humans ; Microbial Sensitivity Tests

To investigate the effects of butyl alcohol extract of Baitouweng Decoction(BAEB) on neutrophil chemotaxis in vaginal mucosa of mice with vulvovaginal candidiasis(VVC). Seventy-two SPF female Kunming mice were randomly divided into normal control group, model group, fluconazole group, BAEB low-dose group, middle-dose group and high-dose group. Subcutaneous injection of estradiol benzoate was conducted to induce pseudo-estrus, and then 2×10~6 CFU·mL~(-1)of Candida albicans was inoculated into vaginal lumen, followed by drug treatment for 7 days. Gram staining was used to observe the morphological changes of C. albicans in vagina; vaginal fungal load was detected on agar plate. Histological changes of vaginal tissues in mice were observed by HE staining. Lactate dehydrogenase(LDH), interleukin-6(IL-6) and tumor necrosis factor(TNF-α) levels in mouse lavage fluid were detected by enzyme-linked immunosorbent assay(ELISA). Neutrophils in vaginal lavage fluid was observed and counted by using Pap smear. The levels of IL-8 and MIP-2 in vaginal mucosa were detected by ELISA. IL-8 and MIP-2 mRNA levels in vaginal mucosa of mice were detected by qRT-PCR. The results showed that as compared with the normal group, VVC model group had a large number of hyphae and a high level of fungal loadinvagina. The vaginal mucosa was completely destroyed, the number of neutrophils increased, and the protein and mRNA levels of IL-8 and MIP-2 were up-regulated. After BAEB treatment, the hyphae of the treatment group was decreased, the fungal load was decreased, the impaired mucosa showed different degrees of improvement, the inflammatory factors were decreased to varying degrees, and the protein and mRNA levels of chemokine IL-8 and MIP-2 were down-regulated. In conclusion, BAEB may be used to treat VVC by inhibiting vulvovaginal candidiasis via blocking neutrophils recruitment into vagina.
1-Butanol ; Animals ; Candida albicans ; Candidiasis, Vulvovaginal/drug therapy* ; Chemotaxis/drug effects* ; Drugs, Chinese Herbal/pharmacology* ; Female ; Mice ; Mucous Membrane/drug effects* ; Neutrophils/drug effects* ; Vagina/diagnostic imaging*

This study aimed to investigate the effect of butyl alcohol extract of Baitouweng Decoction( BAEB) on Candida albicans biofilms based on pH signal pathway. The morphology of biofilms of the pH mutants was observed by scanning electron microscope. The biofilm thickness of the pH mutants was measured by CLSM. The biofilm activity of the pH mutants was analyzed by microplate reader.The biofilm damage of the pH mutants was detected by flow cytometry. The expression of pH mutant biofilm-related genes was detected by qRT-PCR. The results showed that the deletion of PHR1 gene resulted in the defect of biofilm,but there were more substrates for PHR1 complementation. BAEB had no significant effect on the two strains. RIM101 gene deletion or complementation did not cause significant structural damage,but after BAEB treatment,the biofilms of both strains were significantly inhibited. For the biofilm thickness,PHR1 deletion or complementation caused the thickness to decrease,after BAEB treatment,the thickness of the two strains did not change significantly. However,RIM101 gene deletion or complementation had little effect on the thickness,and the thickness of the two strains became thinner after adding BAEB. For biofilm activity,PHR1 deletion or complementation and RIM101 deletion resulted in decreased activity,RIM101 complementation did not change significantly; BAEB significantly inhibited biofilm activity of PHR1 deletion,PHR1 complemetation,RIM101 deletion and RIM101 complemetation strains. For the biofilm damage,PHR1 gene deletion or complementation,RIM101 gene deletion or complementation all showed different degrees of damage; after adding BAEB,the damage rate of PHR1 deletion or complementation was not significantly different,but the damage rate of RIM101 deletion or complementation was significantly increased. Except to the up-regulation of HSP90 gene expression,ALS3,SUN41,HWP1,UME6 and PGA10 genes of PHR1 deletion,PHR1 complementation,RIM101 deletion,and RIM101 complementation strains showed a downward expression trend. In a word,this study showed that mutations in PHR1 and RIM101 genes in the pH signaling pathway could enhance the sensitivity of the strains to the antifungal drug BAEB,thus inhibiting the biofilm formation and related genes expression in C. albicans.
1-Butanol ; Biofilms ; drug effects ; Candida albicans ; drug effects ; Drugs, Chinese Herbal ; pharmacology ; Fungal Proteins ; Gene Expression Regulation, Fungal ; Hydrogen-Ion Concentration ; Plant Extracts ; pharmacology ; Signal Transduction

The aim of this paper was to investigate the inhibitory effect of extract of Coptidis Rhizoma(ECR) on invasion of Candida albicans hyphae in vitro.XTT reduction method was used to evaluate the metabolic activity of C.albicans.The colony edge growth of C.albicans was observed by solid medium.The growth of C.albicans hyphae was determined on semi-solid medium.The morphology and viability changes of C.albicans hyphae were assessed by scanning electron microscope and fluorescence microscope.qRT-PCR method was used to detect the ALS3 and SSA1 expression of C.albicans invasin genes.The results showed that the metabolic viability by XTT method detected that the activity of C.albicans was gradually decreased under the intervention of 64,128 and 256 mg·L-1 of ECR respectively.128,256 mg·L-1 of ECR significantly inhibited colony folds and wrinkles on solid medium and the hyphal invasion in semi-solid medium.Scanning electron microscopy and fluorescence microscopy showed that 128,256 mg·L-1 of ECR could inhibit the formation of C.albicans hyphae.qRT-PCR results showed that the expression of invasin gene ALS3 and SSA1 was down-regulated,and especially 256 mg·L-1 of ECR could down-regulate the two genes expression by 4.8,1.68 times respectively.This study showed that ECR can affect the invasiveness of C.albicans by inhibiting the growth of hyphae and the expression of invasin.
Adenosine Triphosphatases ; genetics ; Candida albicans ; drug effects ; Drugs, Chinese Herbal ; pharmacology ; Fungal Proteins ; genetics ; Gene Expression Regulation, Fungal ; HSP70 Heat-Shock Proteins ; genetics ; Hyphae ; drug effects ; ultrastructure ; Microscopy, Electron, Scanning

OBJECTIVE: To evaluate the synergy of the Burkholderia signaling molecule cis-2-dodecenoic acid (BDSF) and fluconazole (FLU) or itraconazole (ITRA) against two azole-resistant C. albicans clinical isolates in vitro and in vivo. METHODS: Minimum inhibitory concentrations (MICs) of antibiotics against two azole-resistant C. albicans were measured by the checkerboard technique, E-test, and time-kill assay. In vivo antifungal synergy testing was performed on mice. Analysis of the relative gene expression levels of the strains was conducted by quantitative reverse-transcription polymerase chain reaction (qRT-PCR). RESULTS: BDSF showed highly synergistic effects in combination with FLU or ITRA with a fractional inhibitory concentration index of ⪕ 0.08. BDSF was not cytotoxic to normal human foreskin fibroblast cells at concentrations of up to 300 μg/mL. The qRT-PCR results showed that the combination of BDSF and FLU/ITRA significantly inhibits the expression of the efflux pump genes CDR1 and MDR1 via suppression of the transcription factors TAC1 and MRR1, respectively, when compared with FLU or ITRA alone. No dramatic difference in the mRNA expression levels of ERG1, ERG11, and UPC2 was found, which indicates that the drug combinations do not significantly interfere with UPC2-mediated ergosterol levels. In vivo experiments revealed that combination therapy can be an effective therapeutic approach to treat candidiasis. CONCLUSION The synergistic effects of BDSF and azoles may be useful as an alternative approach to control azole-resistant Candida infections.
Antifungal Agents ; pharmacology ; Burkholderia cenocepacia ; chemistry ; Candida albicans ; drug effects ; physiology ; Candidiasis ; drug therapy ; Drug Resistance, Fungal ; Fatty Acids, Monounsaturated ; adverse effects ; Fluconazole ; pharmacology ; Humans ; Microbial Sensitivity Tests ; Triazoles ; metabolism

Antifungal drug resistance is a significant clinical problem, and antifungal agents that can evade resistance are urgently needed. In infective niches, resistant organisms often co-existed with sensitive ones, or a subpopulation of antibiotic-susceptible organisms may evolve into resistant ones during antibiotic treatment and eventually dominate the whole population. In this study, we established a co-culture assay in which an azole-resistant Candida albicans strain was mixed with a susceptible strain labeled with green fluorescent protein to mimic in vivo conditions and screen for antifungal drugs. Fluconazole was used as a positive control to verify the validity of this co-culture assay. Five natural molecules exhibited antifungal activity against both susceptible and resistant C. albicans. Two of these compounds, retigeric acid B (RAB) and riccardin D (RD), preferentially inhibited C. albicans strains in which the efflux pump MDR1 was activated. This selectivity was attributed to greater intracellular accumulation of the drugs in the resistant strains. Changes in sterol and lipid compositions were observed in the resistant strains compared to the susceptible strain, and might increase cell permeability to RAB and RD. In addition, RAB and RD interfered with the sterol pathway, further aggregating the decrease in ergosterol in the sterol synthesis pathway in the MDR1-activated strains. Our findings here provide an alternative for combating resistant pathogenic fungi.
ATP-Binding Cassette Transporters ; genetics ; metabolism ; Antifungal Agents ; chemistry ; metabolism ; pharmacology ; Azoles ; pharmacology ; Biosynthetic Pathways ; drug effects ; genetics ; Candida albicans ; chemistry ; drug effects ; metabolism ; Cell Membrane ; chemistry ; metabolism ; Coculture Techniques ; Drug Resistance, Fungal ; drug effects ; Ergosterol ; metabolism ; Fungal Proteins ; genetics ; metabolism ; Lipids ; chemistry ; Molecular Structure ; Permeability ; Phenyl Ethers ; chemistry ; metabolism ; pharmacology ; Sterols ; chemistry ; metabolism ; Stilbenes ; chemistry ; metabolism ; pharmacology ; Triterpenes ; chemistry ; metabolism ; pharmacology

Adult ; Aged ; Antifungal Agents ; administration & dosage ; adverse effects ; classification ; Candida ; drug effects ; isolation & purification ; Carcinoma ; pathology ; therapy ; Cross Infection ; microbiology ; therapy ; Drug Resistance, Multiple, Fungal ; Female ; Fractures, Bone ; surgery ; Humans ; Male ; Middle Aged ; Mycoses ; microbiology ; therapy ; Patient Care Management ; methods ; Pulmonary Disease, Chronic Obstructive ; complications ; therapy ; Surgical Wound Infection ; microbiology ; therapy ; Symptom Flare Up ; Treatment Outcome

OBJECTIVEMyanmar has a long history of using medicinal plants for treatment of various diseases. To the best of our knowledge there are no previous reports on antiglycation activities of medicinal plants from Myanmar. Therefore, this study was aimed to evaluate the antioxidant, antiglycation and antimicrobial properties of 20 ethanolic extracts from 17 medicinal plants indigenous to Myanmar.

METHODSIn vitro scavenging assays of 2,2-diphenyl-1-picrylhydrazyl (DPPH), nitric oxide (NO), superoxide (SO) radicals were used to determine the antioxidant activities. Folin-Ciocalteu's method was performed to determine the total phenolic content. Antiglycation and antimicrobial activities were detected by bovine serum albumin-fluorescent assay and agar well diffusion method.

RESULTSTerminalia chebula Retz. (Fruit), containing the highest total phenolic content, showed high antioxidant activities with inhibition of 77.98% ± 0.92%, 88.95% ± 2.42%, 88.56% ± 1.87% and 70.74%± 2.57% for DPPH, NO, SO assays and antiglycation activity respectively. It also showed the antimicrobial activities against Staphylococcus aureus, Bacillus cereus, Escherichia coli, Pseudomonas aeruginosa and Candida albicans with inhibition zone of 19, 18, 17, 25 and 15 mm, respectively. Garcinia mangostana Linn. showed the strongest activities for SO and antiglycation assays with inhibition of 93.68% ± 2.63% and 82.37% ± 1.78%. Bark of Melia sp. was the best NO radical scavenger with inhibition rate of 89.39%± 0.60%.

CONCLUSIONThe results suggest that these plants are potential sources of antioxidants with free radical-scavenging and antiglycation activities and could be useful for decreasing the oxidative stress and glycation end-product formation in glycation-related diseases.

Anti-Bacterial Agents ; analysis ; pharmacology ; Anti-Infective Agents ; analysis ; pharmacology ; Antioxidants ; analysis ; pharmacology ; Bacteria ; drug effects ; growth & development ; Biphenyl Compounds ; metabolism ; Candida albicans ; drug effects ; growth & development ; Fruit ; Garcinia ; chemistry ; Glycation End Products, Advanced ; metabolism ; Humans ; Magnoliopsida ; chemistry ; Medicine, Traditional ; Melia ; chemistry ; Myanmar ; Nitric Oxide ; metabolism ; Oxidative Stress ; drug effects ; Phenols ; analysis ; pharmacology ; Phytotherapy ; Picrates ; metabolism ; Plant Bark ; Plant Extracts ; chemistry ; pharmacology ; Plants, Medicinal ; Superoxides ; Terminalia ; chemistry

OBJECTIVESThis study aimed to evaluate the in vitro antioxidant capacity, to determine the anti-inflammatory effect due to lipoxygenase inhibition and to test the antimicrobial activity of ethanolic extracts from leaves of seven climbing species belonging to the Bignoniaceae family. These species are Adenocalymma marginatum (Cham.) DC., Amphilophium vauthieri DC., Cuspidaria convoluta (Vell.) A. H. Gentry, Dolichandra dentata (K. Schum.) L. G. Lohmann, Fridericia caudigera (S. Moore) L. G. Lohmann, Fridericia chica (Bonpl.) L. G. Lohmann and Tanaecium selloi (Spreng.) L. G. Lohmann.

METHODSThe antioxidant activity was evaluated using three methods, 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS), 2,2-diphenyl-1-picrylhydrazyl (DPPH), and ferric reducing antioxidant power. Lipoxygenase-inhibiting activity was assayed spectrophotometrically; the result was expressed as percent inhibition. The antimicrobial activity was assessed using the agar disk diffusion method. Minimal inhibitory concentration (MIC) and minimal bactericidal/fungicidal concentration were also determined for each extract against 12 pathogenic bacterial strains of Staphylococcus aureus and seven fungal strains of the Candida genus. The identification of the major compounds present in the most promising extract was established by high-performance liquid chromatography-tandem mass spectrometry.

RESULTSC. convoluta, F. caudigera, and F. chica exhibited the best antioxidant activity by scavenging DPPH and ABTS radicals and reducing Fe ion. These extracts showed a notable inhibition of lipoxygenase. F. caudigera was found to have the lower MIC value against S. aureus strains and six Candida species. The extracts of F. caudigera and C. convoluta were active even against methicillin-resistant S. aureus. C. convoluta had higher total phenol content, better antioxidant activity and superior anti-inflammatory and antimicrobial activity. The main phenolic compounds found in this extract were coumaric and hydroxybenzoic acid derivatives and glycosylated and nonglycosylated flavones.

CONCLUSIONMost of the extracts exhibited antioxidant activity as well as in vitro inhibition of lipoxygenase. The excellent antimicrobial activity of T. selloi and F. chica supports their use in traditional medicine as antiseptic agents. The extracts of F. caudigera and C. convoluta, both with notable biological activities in this study, could be used as herbal remedies for skin care. In addition, this study provides, for the first time, information about phenolic compounds present in C. convoluta.

Anti-Infective Agents ; chemistry ; pharmacology ; Antioxidants ; chemistry ; pharmacology ; Bignoniaceae ; chemistry ; Candida ; drug effects ; growth & development ; Humans ; Lipoxygenase ; chemistry ; Lipoxygenase Inhibitors ; chemistry ; pharmacology ; Medicine, Traditional ; Microbial Sensitivity Tests ; Plant Extracts ; chemistry ; pharmacology ; Staphylococcus aureus ; drug effects ; growth & development

OBJECTIVE: To evaluate the efficacy of cis-2-dodecenoic acid (BDSF) in the treatment and prevention of vaginal candidiasis in vivo. METHODS: The activities of different concentrations of BDSF against the virulence factors of Candida albicans (C. albicans) were determined in vitro. An experimental mouse model of Candida vaginitis was treated with 250 μmol/L BDSF. Treatment efficiency was evaluated in accordance with vaginal fungal burden and inflammation symptoms. RESULTS: In vitro experiments indicated that BDSF attenuated the adhesion and damage of C. albicans to epithelial cells by decreasing phospholipase secretion and blocking filament formation. Treatment with 30 μmol/L BDSF reduced the adhesion and damage of C. albicans to epithelial cells by 36.9% and 42.3%, respectively. Treatment with 200 μmol/L BDSF completely inhibited phospholipase activity. In vivo mouse experiments demonstrated that BDSF could effectively eliminate vaginal infection and relieve inflammatory symptoms. Four days of treatment with 250 μmol/L BDSF reduced vaginal fungal loads by 6-fold and depressed inflammation. Moreover, BDSF treatment decreased the expression levels of the inflammatory chemokine-associated genes MCP-1 and IGFBP3 by 2.5- and 2-fold, respectively. CONCLUSION BDSF is a novel alternative drug that can efficiently control vaginal candidiasis by inhibiting the virulence factors of C. albicans.
Animals ; Candida albicans ; drug effects ; metabolism ; pathogenicity ; physiology ; Candidiasis, Vulvovaginal ; drug therapy ; genetics ; immunology ; microbiology ; Chemokine CCL2 ; genetics ; immunology ; Disease Models, Animal ; Fatty Acids, Monounsaturated ; administration & dosage ; Female ; Fungal Proteins ; genetics ; metabolism ; Humans ; Insulin-Like Growth Factor Binding Protein 3 ; genetics ; immunology ; Mice ; Virulence ; drug effects ; Virulence Factors ; genetics ; metabolism