Cardiac Toxicity of Azole Antifungals

Cardiac toxicity is an uncommon side effect of anti-fungal therapy. Until the recent reports of itraconazole (ITZ) associated cardiac failure, amphotericin was the antifungal most frequently reported with arrhythmias. We evaluated the cardiac effect of azole antifungals, specifically ITZ, and possible mechanisms of toxicity. Ex vivo live-heart studies were performed utilizing Sprague Dawley rats. Short exposure (<5 minutes), random crossover, dose ranging studies were performed with each pharmacologic agent. ITZ focused trials also included dose ranging utilizing a non-crossover design. The only azole found to have significant toxicity was ITZ. At ITZ ~ ED25 (2 - 2.5 ug/mL) exposures, contractility decreased by 22.2% ± 15.7% and amplitude of left ventricular pressure decreased by 11% ± 0.17%. Electron micrograph and alterations in mitochondrial respiration suggest mitochondrial toxicity as an underlying mechanism. In conclusion, ITZ was associated with reductions in contractility, possibly secondary to mitochondrial dysfunction and dilated cardiomyopathy.

Antifungal pipeline:Is there light at the end of the tunnel?

The misuse and overuse of classic antifungals have accelerated the development of resistance mechanisms,diminishing the efficacy of established therapeutic pathways and necessitating a shift towards alternative targets.Despite this pressing need for new treatments,the antifungal drug pipeline has been largely stagnant for the past three decades,primarily due to the high risks and costs associated with antifungal drug development,compounded by uncertain market returns.Extensive research durations,special patient populations and rigorous regulatory demands pose significant barriers to bringing novel antifungal agents to market.In response,the“push-pull”incentive model has emerged as a vital strategy to invigorate the pipeline and encourage innovation.This editorial critically examines the current clinical landscape and spotlights emerging antifungal agents,such as Fosmanogepix,Ibrexafungerp,and Olorofim,while also unraveling the multifaceted challenges faced in new antifungal drug development.The generation of novel antifungals offers a beacon of hope in the battle against antimicrobial resistance,but it is premature to declare them as definitive solutions.Their future role hinges on thorough clinical validation,costeffectiveness assessments,and continuous post-marketing surveillance.Only through strategic implementation and integration with market strategies we can transform the landscape of antifungal development,addressing both the resistance crisis and the treatment challenges.

Bioactive chemical constituents from the marine-derived fungus Cladosporium sp.DLT-5

A new isochromanone,cladosporinisochromanone(1),accompanied by 15 known compounds(2–16)were obtained from secondary metabolites produced by marine-derived fungus Cladosporium sp.DLT-5.NMR and HRESIMS spectra elucidation determined the planar structure of 1.Subsequent electronic circular dichroism(ECD)experiment assigned the absolute configuration of 1.Compounds 1,2,4–6,and 10 displayed different degrees of neuroprotective activities on human neuroblastoma cells SH-SY5Y.Five compounds(1,3–5,and 13)emerged resistance to protein tyrosine phosphatase 1B(PTP1B),further kinetic analysis and molecular docking study indicated that the most potent compound 13(IC50value of 10.74±0.61μmol/L)was found as a noncompetitive inhibitor for PTP1B.Surface plasmon resonance(SPR)and molecular docking studies also demonstrated the interaction between compound 12 and Niemann-Pick C1 Like 1(NPC1L1),which has been identified as significant therapeutic target for hypercholesteremia.In addition,compounds 3,6,and 14 showed attractive inhibitory activity against the phytopathogenic fungi:Colletotrichum capsici.Therefore,library of Cladosporium metabolites is enriched and new active uses of known compounds are explored.

Curcuminoids Inhibit Botrytis cinerea and Colletotrichum gloeosporioides

The growth rate method was adopted to measure the inhibitory effect of curcumin,tetrahydrocurcumin,demethoxycurcumin,and bisdemethoxycurcumin on the mycelial growth of Botrytis cinerea and Colletotrichum gloeosporioides.The results showed that the four curcuminoids inhibited the mycelial growth of the two pathogens in a concentration-dependent manner.Bisdemethoxycurcumin at 600 mg/L exerted the strongest inhibitory effect on the mycelial growth of B.cinerea and C.gloeosporioides,with the relative inhibition rates of 98.19%and 100%,respectively;followed by demethoxycurcumin;curcumin exerted the worst inhibitory effect.Toxicity test results also showed that four curcuminoids all had a certain toxicity to B.cinerea and C.gloeosporioides,among which,bisdemethoxycurcumin exhibited the strongest toxicity,with the EC_(50)of 131.125 and 122.235 mg/L,respectively;while curcumin had the lowest toxicity,with the EC_(50)of 273.143 and 194.943 mg/L,respectively.

Assessing the Efficacy of Lemongrass (Cymbopogon citratus) and Sambong (Blumea balsamifera) Extracts in Combating Black Pod Disease: Sustainable Solutions for Controlling Phytophthora megakarya in Cameroon’s Cocoa Plantations

The use of plant extracts as antifungal agents is gaining increasing attention, particularly for the control of black pod disease in cocoa. Despite extensive research, current strategies haven’t been entirely effective. This study evaluated the effectiveness of Cymbopogon citratus and Blumea balsamifora leaf extracts, both individually and in combination, against Phytophthora megakarya. We assessed the efficacy of the most promising combination (75% B. balsamifera, 25% C. citratus) after storage at room temperature for up to 9 days. Agar microdilution and in vivo bioassays were conducted to determine antifungal susceptibility and effectiveness. Blumea extract exhibited the highest overall inhibitory activity, with the lowest minimum inhibitory concentration (117 µl mL−1) while C. citratus had a narrower range of MIC (146 to 233 µl mL−1). The combination of C. citratus and B. balsamifera demonstrated a synergistic effect against P. megakarya, achieving growth inhibition on V8 media (92.72 ± 4.20% to 100%) and on artificially infected detached pod cortex (92.24 ± 4.53% to 98.75 ± 1.25%), which was not significantly different from the positive control (Ridomil). Furthermore, this combination maintained its effectiveness for up to 9 days at room temperature. These findings suggest that combining plant extracts can enhance their antifungal properties.

Biocontrol of Aspergillus flavus Strains Isolated from Bambara Groundnut (Vigna subterranea (L.) Verdc.) Seeds Using Essential Oils of Lippia multiflora Moldenke, Ocimum americanum L. (Lamiaceae) and Eucalyptus cameldulensis Dehnh

In nature, plant extracts play a crucial role in defending plants against biotic and abiotic stressors. Moreover, the use of plant-based products, such as plant extracts, represents a promising alternative to synthetic fungicides, which pose potential health risks to consumers. In this study, the antifungal activity of the essential oils (EOs) of Lippia multiflora, Eucalyptus camaldulensis and Ocimum americanum was evaluated against two strains of Aspergillus flavus via the agar dilution method. These two Aspergillus flavus fungi was isolated from Bamabra groundnut seeds. Lippia multiflora essential oil (EO) showed the best results compared with the other oils, with a minimum inhibitory concentration (MIC) of 9000 μg∙mL−1. The MIC for Eucalyptus camaldulensis and Ocimum americanum EOs was 10,800 μg∙mL−1. In view of their antifungal properties, these EOs could be used to develop a new, safe antifungal agent for food preservation.

Candidemia chronicles:Retrospective analysis of candidemia epidemiology,species distribution,and antifungal susceptibility patterns in Bahrain

BACKGROUND Invasive fungal infections,particularly candidemia,pose significant clinical challenges globally.Understanding local epidemiology,species distribution,and antifungal susceptibility patterns is crucial for effective management despite regional variations.AIM To investigate the epidemiology,species distribution,antifungal susceptibility patterns,and associated risk factors of candidemia among patients in Bahrain from 2021 to 2023.METHODS This retrospective study analyzed demographic data,Candida species distribution,antifungal susceptibility profiles,and risk factors among candidemia patients treated at a tertiary care hospital in Bahrain over three years.Data was collected from medical records and analyzed using descriptive statistics.RESULTS A total of 430 candidemia cases were identified.The mean age of patients was 65.7 years,with a mortality rate of 85.5%.Candida albicans(C.albicans)was the most common species,followed by Candida parapsilosis,Candida tropicalis(C.tropicalis),and emerging multidrug-resistant Candida auris(C.auris).Antifungal susceptibility varied across species,with declining susceptibility to azoles observed,particularly among C.albicans and C.tropicalis.Major risk factors included central venous catheters,broad-spectrum antibiotics,and surgical procedures.CONCLUSION This study highlights the substantial burden of candidemia among older adults in Bahrain,characterized by diverse Candida species.It also concerns levels of antifungal resistance,notably in C.auris.The findings underscore the importance of local epidemiological surveillance and tailored treatment strategies to improve outcomes and mitigate the spread of multidrug-resistant Candida species.Future research should focus on molecular resistance mechanisms and optimizing therapeutic approaches to address this growing public health concern.

Global Burden of Fungal Infections and Antifungal Resistance from 1961 to 2024: Findings and Future Implications

Background: Antifungal resistance (AFR) is a global public health problem with devastating effects, especially among immunocompromised individuals. Addressing AFR requires a One Health approach including Antifungal Stewardship (AFS). This study aimed to comprehensively review global studies published on fungal infections and AFR and to recommend solutions to address this growing problem. Materials and Methods: This was a narrative review that was conducted using published papers on fungal infections, AFR, and AFS between January 1961 and March 2024. The literature was searched using PubMed, Google Scholar, Web of Science, and EMBASE. Results: This found that there has been an increase in fungal infections globally, especially among immunocompromised patients. Due to this increase in fungal infections, there has been a proportionate increase in the use of antifungal agents to prevent and treat fungal infections. This increased use of antifungal agents has worsened the problem of AFR contributing to increased morbidity and mortality. Globally, fungal infections have contributed to 150 million infections annually and 1.7 million deaths per year. By the year 2023, over 3.8 million people died from fungal infections. Addressing AFR remains a challenge because the treatment of antifungal-resistant infections is difficult. Finally, the treatment of fungal infections is a global challenge exacerbated by the limited number of antifungal agents to treat invasive fungal infections. Conclusion: The results of this study indicated that fungal infections and AFR are prevalent across humans, animals, agriculture, and the environment. Addressing this problem requires the provision of solutions such as improving the awareness of AFR, conducting further research on the discovery of new antifungal agents, and implementing AFS programs. If this global problem is not addressed, the morbidity and mortality associated with AFR will continue to rise in the future.

Antimicrobial and synergistic effects of lemongrass and geranium essential oils against Streptococcus mutans,Staphylococcus aureus,and Candida spp.

BACKGROUND The oral cavity harbors more than 700 species of bacteria,which play crucial roles in the development of various oral diseases including caries,endodontic infection,periodontal infection,and diverse oral diseases.AIM To investigate the antimicrobial action of Cymbopogon Schoenanthus and Pelargonium graveolens essential oils against Streptococcus mutans,Staphylococcus aureus,Candida albicans,Ca.dubliniensis,and Ca.krusei.METHODS Minimum microbicidal concentration was determined following Clinical and Laboratory Standards Institute documents.The synergistic antimicrobial activity was evaluated using the Broth microdilution checkerboard method,and the antibiofilm activity was evaluated with the 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide assay.Data were analyzed by one-way analysis of variance followed by the Tukey post-hoc test(P≤0.05).RESULTS C.schoenanthus and P.graveolens essential oils were as effective as 0.12%chlorhexidine against S.mutans and St.aureus monotypic biofilms after 24 h.After 24 h P.graveolens essential oil at 0.25%was more effective than the nystatin group,and C.schoenanthus essential oil at 0.25%was as effective as the nystatin group.CONCLUSION C.schoenanthus and P.graveolens essential oils are effective against S.mutans,St.aureus,Ca.albicans,Ca.dubliniensis,and Ca.krusei at different concentrations after 5 min and 24 h.

Epidemiology, Clinical Features and Antifungal Resistance Profile of Candida auris in Africa: Systematic Review

Candida auris since it discovery in 2009 is becoming a severe threat to human health due to its very quickly spread, its worldwide high resistance to systemic antifungal drugs. In resource-constrained settings where several conditions are met for its emergence and spread, this worrisome fungus could cause large hospital and/or community-based outbreaks. This review aimed to summarize the available data on C. auris in Africa focusing on its epidemiology and antifungal resistance profile. Major databases were searched for articles on the epidemiology and antifungal resistance profile of C. auris in Africa. Out of 2,521 articles identified 22 met the inclusion criteria. In Africa, nearly 89% of African countries have no published data on C. auris. The prevalence of C. auris in Africa was 8.74%. The case fatality rate of C. auris infection in Africa was 39.46%. The main C. auris risk factors reported in Africa were cardiovascular disease, renal failure, diabetes, HIV, recent intake of antimicrobial drugs, ICU admissions, surgery, hemodialysis, parenteral nutrition and indwelling devices. Four phylogenetic clades were reported in Africa, namely clades I, II, III and IV. Candida auris showed a pan-African very high resistance rate to fluconazole, moderate resistance to amphotericin B, and high susceptibility to echinocandins. Finally, C. auris clade-specific mutations were observed within the ERG2, ERG3, ERG9, ERG11, FKS1, TAC1b and MRR1 genes in Africa. This systematic review showed the presence of C. auris in the African continent and a worrying unavailability of data on this resilient fungus in most African countries.

A Bronchopulmonary Onset of Candidemia Revealing a Granulomatosis with Polyangiitis

Candidemia is defined as being a yeast infection confirmed by the presence of at least one positive Candida blood culture. It is a life threatening infection causing high mortality. The clinical signs are generally compatible with the causative agent (whether there is a deep venous catheter or not). On the other hand and according to the 2012 Revised Chapel Hill Classification, granulomatosis with polyangiitis GPA is classified as a vasculitis associated with antineutrophil cytoplasmic antibodies ANCA. It is a systemic disease characterized by the anatomopathological aspect of granuloma. We report the case of a patient who presented an atypical and a very rare revealing mode of GPA which was a bronchopulmonary candidiasis complicated by candidemia. Despite its controversy, the combination in the acute phase of antifungal treatment based on intravenous voriconazole and glucocorticoid therapy has made it possible to control candidemia and calm vasculitis.

Antifungal Activity of Extracts from Clerodendrum Bungei Leaves against Two Species of Phytopathogens

The test was undertaken to reveal the antifungal activity of extracts from Clerodendrum bungei leaves against Pestalotia and Rhizoctonia solani, the results showed that optimal condition for best antifungal activity of extracts against pestalotia and Rhizoctonia solani are as follows： material-liquid ratio of 1：6,75% ethanol as extracting solvent, reflux at 90℃ for 1.5 h. The substances with good dissolubility in ethanol and water solution such as organic acid, bioflavonoid and alkaloid are main antifungal bioactive substances in Clerodendrun bungei.

A New Antifungal Flavonol Glycoside from Hypericum perforatum

In addition to six known flavonoids quercitrin, hyperoside, avicularin, rutin, quercetin and kaemferol, a new flavonol glycoside named 6″_O_acetyl quercetin 3_O_β_ D _alloside (1) was isolated from the aerial parts of Hypericum perforatum L. The structures were determined on the basis of spectroscopic methods (UV, IR, FAB_MS, 1H_NMR and 13 C NMR). Antifungal assay of all compounds showed that metabolite 1, quercitrin and quercetin were inhibitory to the growth of phytopathogenic fungus Helminthosporium sativum Pamel King et Bakke with minimum inhibitory concentrations (MICs) of 25, 50 and 50 μg/mL, respectively. Moreover, glycoside 1 and quercitrin were also shown to be able to inhibit the growth of Fusarium graminearum Schw. with MIC of 100 μg/mL. The MICs of ketoconazole used as control against the test fungi were 0.5 μg/mL in our assay.

Screening of Two Biocontrol Strains of Bacillus subtilis against Ginseng Soil-borne Disease and Their Antifungal Activities

[ Objective] The paper was to obtain biocontrol strains with good control effects against ginseng soil-borne disease through screening. [ Method] Dilu- tion plate method and plate confrontation culture method were used to isolate and screen biocontrol bacteria from the rhizosphere soil of diseased ginseng. The strains were identified through morphology, physiological and biochemical characteristics and 16S rDNA. [ Result ] With Rhizoctonia solani, Fusarium oxysporum and Fu- sarium solani as the indicator strains, two biocontrol strains B59 and X1 with strong antagonistic effects were screened from the rhizosphere soil of diseased ginseng in Tieli farm of Heilongjiang Province, and they were identified to be Bacillus subtilis. The inhibition rates of two biocontrol strains against eight different fungi were all greater than 90%. The primary study indicated that B59 and X1 strains could secrete antifungal active substances. [ Conclusion] Two biocontrol Bacillus subti- lis strains 1359 and X1 all had strong antagonistic effect against ginseng soil-borne disease, which had certain potential for development and utilization.

Synthesis of a New Series of Chalcone Derivatives and Their Antifungal Activities

To study the antifungal effect of chalcone derivatives. Methods Sixteenchalcone derivatives were synthesized and confirmed by ~1H NMR and IR spectra, and tested forantifungal activity against four common pathogenic fungi. Their structure-activity relationship isdiscussed. Results Among 16 title compounds, there were 5 new compounds, which have not beenreported before. The preliminary antifungal test showed that all title compounds exhibitedantifungal activities to a certain extent. The activity of compound 8 against Trichophyton rubrumhad a potency equal to that of fluconazole, with a MIC of 4 μg·mL^(-1) . Conclusion Sixteenchalcones were prepared and their antifungal activities against four common pathogenic fungi invitro were examined. Some of them exhibited antifungal activities to a certain extent.

Inhibitive Activity of the Extracts of Plants in Artemisia against Fusarium oxysporum f. sp. vasinfectum and Fusarium momiliforme

[Objective]The aim was to provide theoretical basis for the control of cotton Fusarium wilt and cotton boll rot disease.[Method]The inhibitory activity of the extracts from three species of plants(Artemisia annual L.,Artemisia capillaris Thunb.,Artemisia argyi Levl.et Vant)against Fusarium oxysporum f.sp.vasinfectum and Fusarium moniliforme were studied under the condition of laboratory.[Result]The extracts of all the three plants in Artemisia showed strong antifungal activity against the tested pathogenic ...

Synergism and Field Efficacy of Mixed Preparations of Pyraclostrobin and Tebuconazole to Glomerella cingulata

[Objective] This study was conducted to screen high-efficient low-toxicity new compound preparation for control of Glomerella cingulata. [Method] The toxicity of pyraclostrobin, tebuconazole and their mixed preparations to Glomerella cingulata was determined by mycelial growth rate method, and their control effects on Glomerella cingulata were evaluated by field efficacy test. [Result] The mixed preparations of pyraclostrobin and tebuconazole at mass ratios of 5：1, 3：1, 1：1, 1：3 and 1：5 exhibited ECso values to mycelial growth of Glomerella cingulata of 0.612 9, 0.530 1, 0.232 6, 0.232 8 and 0.329 6 iJg/ml, respectively; and the 5 preparations exhibit- ed synergistic coefficients （SRs） to Glomerella cingulata of 1.29, 1.33, 2.29, 1.84 and 1.22, respectively, and among them, the preparation with mass ratio of 1：1 showed the highest synergism. The field efficacy test showed that the field control effects of 1 000 times, 2 000 times and 3 000 times dilutions of 25% pyraclostrobin-tebuconazole suspension, 5 000 times dilution of 430 g/L tebuconazole suspension and 2 000 times dilution of 250 g/L pyraclostrobin EC were 91.54%, 90.80%, 82.88%, 76.43% and 74.10%, respectively. [Conclusions] Therefore, the mixed preparations of pyraclostrobin and tebuconazole showed remarkable synergism on control of Glomerella cingulata, and preparation with the mixing ratio of 1：1 exhibited the most significant synergism on Glomerella cingulata. For soaking treatment to fruit clusters with 1 000-2 000 times dilution of 25% pyraclostrobin .tebuconazole suspension, the field efficacy to Glomerella cingulata was over 90%.

Screening and Identification of Myxobacterias with Antifungal Activity

[ Objective] The paper was to screen myxobacteria with antifungal activity, and identify its species. [ Method] 237 myxobacteria were isolated and pu- rified from 200 copies of soil samples collected from 23 provinces in China. The strains were fermented in four different media, and the fermentation products were extracted by methanol to obtain metabolites. With Candida albicans as the model, the secondary metabolites were carried out high-throughput screening. [ Result ] A strain of myxohacteria numbered ZJ2 was obtained after secondary screening, its secondary metabolites had activities against G. albicans. 16S rDNA cloning and sequencing results showed that ZJ2 was Myxococcus fidvus. [ Conclusion ] The secondary metabolites of ZJ2 strain had bioactive substances with significant inhibi- tion effect against the growth of C. albicans, which had potential pharmaceutical research and development value.

Isolation and Identification of Antifungal Bacterial Strain KL-1 against Plant Wilt Disease

[Objective] The antifungal bacteria of plant wilt disease was screened and identified to provide foundation for the study on bio-control preparation of plant wilt disease.[Method] Confrontation culture method was adopted to screen the bio-control bacteria with good antifungal effect against plant wilt disease,Biolog bacteria automatic identification system and 16S rDNA sequence analysis method were selected to identify its taxonomic status,the biological safety of the strain towards cotton and mice was also determined.[Result] 12 bacterial strains were isolated from rhizosphere of cotton.Among those strains,5 isolates showed antifungal activity against F.decemcellulare Brick,F.oxysporum f.sp.Diathi,F.oxysporum f.sp.vasinfectum.The antifungal effect of KL-1 strain against three target strains of pathogen reached 69.09%,80.78% and 78.89% respectively.Identification results of Biolog bacteria automatic identification system and 16S rDNA sequence analysis method showed that KL-1strain was Bacillus amyloliquefaciens;primary determination results of biological safety also showed that the strain KL-1 was safe and non-toxic towards cotton and mice.[Conclusion] KL-1strain of B.amyloliquefaciens had antifungal effect against several pathogens of plant wilt diseases,which was safe and non-toxic towards cotton and mice,being the bio-control strain with research and development potential.

Antifungal Effect of Streptomyces 702 Antifungal Monomer Component DZP8 on Rhizoctonia solani and Magnaporthe grisea

The aim of this study was to investigate the in vitro antifungal effects of antifungal monomer component DZP8 isolated from Streptomyces 702 on the mycelium growth, sclerotium formation and germination of Rhizoctonia solani and on the mycelium growth, conidial formation, germination, appressorium formation of Magnaporthe grisea. The results showed that the antifungal monomer component DZP8 has strong antifungal effect on both the R. solani and M. grisea. The EC50 and EC90 of DZP8 were 1.81 and 3.35 μg/ml on Ft. solani respectively, and 37.01 and 136.21 μg/ml on M. grisea respectively. Under the treatment of 48.01 μg/ml DZP8, the sclerotium formation rate of R. solani was just 39.21%, the formation time delayed by 216 h and the dry weight decreased by 81.37% in comparison the con- trol; and 33.51 μg/ml DZP8 significantly inhibited the sclerotium germination. In the presence of 160.08 μg/ml DZP8, the sporulation of M. grisea was just 9.29% of control sample; 20.14 μg/ml DZP8 inhibited the conidial germination suppression rate by 95.16%, and the appressorium formation by 100%.