Class Of Antifungal Agents Research Articles

Siderophore-Conjugated Antifungals: A Strategy to Potentially Cure Fungal Infections.

Fungi pose a global threat to humankind due to the increasing emergence of multi-drug-resistant fungi. There is a rising incidence of invasive fungal infections. Due to the structural complexity of fungal cell membranes, only a few classes of antifungal agents are effective and have been approved by the U.S. FDA. Hence, researchers globally are focusing on developing novel strategies to cure fungal infections. One of the potential strategies is the "Trojan horse" approach, which uses the siderophore-mediated iron acquisition (SIA) system to scavenge iron to deliver potent antifungal agents for therapeutics and diagnostics. These siderophore conjugates chelate to iron and are taken up through siderophore-iron transporters, which are overexpressed exclusively on microbes such as bacteria or fungi, but not mammalian cells. Our comprehensive review delves into recent advancements in the design of siderophore-conjugated antifungal agents to gain fungal cell entry. Notably, our focus extends to unraveling the intricate relationship between the structure of natural siderophores or siderophore-like molecules and the resulting antifungal activity. By exploring these design strategies, we aim to contribute to the ongoing discourse on combating drug-resistant fungal infections and advancing the landscape of antifungal theranostics.

Antifungal Susceptibility Pattern of Fungi Isolated from Patients with Otomycosis Attending a Tertiary Health Care Institution in Sokoto, Nigeria

Abstract Background: Antifungal therapy is an important component of patient management for acute and chronic mycoses. However, treatment choices are restricted because of the scanty number of antifungal drug classes. Medical treatment of otomycosis is further compromised by the emergence of antifungal drug resistance, and these limits available drug classes as treatment options. Once considered a rare occurrence, antifungal drug resistance is on the rise in many high-risk medical centers. Most concerning is the evolution of multidrug-resistant organisms refractory to several different classes of antifungal agents, especially among common Candida species. Aim: This study seeks to identify the fungal species implicated in otomycosis among patients attending a tertiary health-care institution in Sokoto, Nigeria and determine its susceptibility pattern using commonly used antifungal agents. Methods: A descriptive, cross-sectional, hospital-based study was conducted on 100 patients with otitis externa. The ear discharge specimens were collected and analyzed using the standard microbial techniques. The antibiotic susceptibility profiles were determined for 12 different antifungal by the standard disk diffusion method. Data were analyzed using the SPSS software version 25 and the P < 0.05 was considered as statistically significant. Results: One hundred and twenty-four external ear discharge samples were collected from either right ear, left ear, or both ears (some patients has unilateral while others have bilateral disease and those with bilateral disease, samples were taken from the two ears). Aspergillus niger 30 (40.0%) was the most commonly isolated fungi in this study, followed by Candida spp. 25 (33.3%), Aspergillus fumigatus 5 (6.7%), Mucor 5 (6.7%), Penicillum 4 (5.3%), Aspergillus flavus 3 (4.0%), and Rhizopus 3 (4.0%) %). The isolated fungi were tested for antifungal sensitivity to 6 antifungal discs. A. niger shows good susceptibility to clotrimazole (100%), nystatin (90%), and fluconazole (83.3%) but was resistant to griseofulvin, terbinafine, and ketoconazole. A. flavus and A. fumigatus also show good sensitivity to clotrimazole, nystatin, and fluconazole. Candida albicans was only susceptible to clotrimazole but resistant to other tested antifungal disc. Rhizopus and Penicillum species showed 100.0% sensitivity to clotrimazole but also resistant to other tested antifungal discs. Conclusions: This study revealed that Aspergillus and Candida species were the most common fungal pathogens causing otomycosis. A. niger is the predominant fungal isolate. Molds isolates showed good susceptibility to clotrimazole, while highest resistance was to terbinafine and ketoconazole. Yeasts isolates showed highest susceptibility to clotrimazole and highest resistance to nystatin and fluconazole.

Microevolution of Candida glabrata (Nakaseomyces glabrata) during an infection

Candida glabrata (Nakaseomyces glabrata) is an emergent and opportunistic fungal pathogen that colonizes and persists in different niches within its human host. In this work, we studied five clinical isolates from one patient (P7), that have a clonal origin, and all of which come from blood cultures except one, P7-3, obtained from a urine culture. We found phenotypic variation such as sensitivity to high temperature, oxidative stress, susceptibility to two classes of antifungal agents, and cell wall porosity. Only isolate P7-3 is highly resistant to the echinocandin caspofungin while the other four isolates from P7 are sensitive. However, this same isolate P7-3, is the only one that displays susceptibility to fluconazole (FLC), while the rest of the isolates are resistant to this antifungal. We sequenced the PDR1 gene which encodes a transcription factor required to induce the expression of several genes involved in the resistance to FLC and found that all the isolates encode for the same Pdr1 amino acid sequence except for the last isolate P7-5, which contains a single amino acid change, G1099C in the putative Pdr1 transactivation domain. Consistent with the resistance to FLC, we found that the CDR1 gene, encoding the main drug efflux pump in C. glabrata, is highly overexpressed in the FLC-resistant isolates, but not in the FLC-sensitive P7-3. In addition, the resistance to FLC observed in these isolates is dependent on the PDR1 gene. Additionally, we found that all P7 isolates have a different proportion of cell wall carbohydrates compared to our standard strains CBS138 and BG14. In P7 isolates, mannan is the most abundant cell wall component, whereas β-glucan is the most abundant component in our standard strains. Consistently, all P7 isolates have a relatively low cell wall porosity compared to our standard strains.These data show phenotypic and genotypic variability between clonal isolates from different niches within a single host, suggesting microevolution of C. glabrata during an infection.

In Silico Analysis of Natural Plant-Derived Cyclotides with Antifungal Activity against Pathogenic Fungi.

Fungal infections in plants, animals, and humans are widespread across the world. Limited classes of antifungal drugs to treat fungal infections and loss of drug efficacy due to rapidly evolving fungal strains pose a challenge in the agriculture and health sectors. Hence, the search for a new class of antifungal agents is imperative. Cyclotides are cyclic plant peptides with multiple bioactivities, including antifungal activity. They have six conserved cysteine residues forming three disulfide linkages (CI-CIV, CII-CV, CIII-CVI) that establish a Cyclic Cystine Knot (CCK) structure, making them extremely resistant to chemical, enzymatic, and thermal attacks. This in silico analysis of natural, plant-derived cyclotides aimed to assess the parameters that can assist and hasten the process of selecting the cyclotides with potent antifungal activity and prioritize them for in vivo/ in vitro experiments. The objective of this study was to conduct in silico studies to compare the physicochemical parameters, sequence diversity, surface structures, and membrane-cyclotide interactions of experimentally screened (from literature survey) potent (MIC ≤ 20 μM) and non-potent (MIC > 20 μM) cyclotides for antifungal activity. Cyclotide sequences assessed for antifungal activity were retrieved from the database (Cybase). Various online and offline tools were used for sequence-based studies, such as physicochemical parameters, sequence diversity, and neighbor-joining trees. Structure-based studies involving surface structure analysis and membrane-cyclotide interaction were also carried out. All investigations were conducted in silico. Physicochemical parameter values, viz. isoelectric point, net charge, and the number of basic amino acids, were significantly higher in potent cyclotides compared to non-potent cyclotides. The surface structure of potent cyclotides showed a larger hydrophobic patch with a higher number of hydrophobic amino acids. Furthermore, the membrane-cyclotide interaction studies of potent cyclotides revealed lower transfer free energy (ΔG transfer) and higher penetration depth into fungal membranes, indicating higher binding stability and membrane-disruption ability. These in silico studies can be applied for rapidly identifying putatively potent antifungal cyclotides for in vivo and in vitro experiments, which will ultimately be relevant in the agriculture and pharmaceutical sectors.

Fungal Drug Response and Antimicrobial Resistance

Antifungal resistance is a growing concern as it poses a significant threat to public health. Fungal infections are a significant cause of morbidity and mortality, especially in immunocompromised individuals. The limited number of antifungal agents and the emergence of resistance have led to a critical need to understand the mechanisms of antifungal drug resistance. This review provides an overview of the importance of antifungal resistance, the classes of antifungal agents, and their mode of action. It highlights the molecular mechanisms of antifungal drug resistance, including alterations in drug modification, activation, and availability. In addition, the review discusses the response to drugs via the regulation of multidrug efflux systems and antifungal drug-target interactions. We emphasize the importance of understanding the molecular mechanisms of antifungal drug resistance to develop effective strategies to combat the emergence of resistance and highlight the need for continued research to identify new targets for antifungal drug development and explore alternative therapeutic options to overcome resistance. Overall, an understanding of antifungal drug resistance and its mechanisms will be indispensable for the field of antifungal drug development and clinical management of fungal infections.

Potential Strategies to Control the Risk of Antifungal Resistance in Humans: A Comprehensive Review

Fungal infections are becoming one of the main causes of morbidity and mortality in people with weakened immune systems. Mycoses are becoming more common, despite greater knowledge and better treatment methods, due to the regular emergence of resistance to the antifungal medications used in clinical settings. Antifungal therapy is the mainstay of patient management for acute and chronic mycoses. However, the limited availability of antifungal drug classes limits the range of available treatments. Additionally, several drawbacks to treating mycoses include unfavourable side effects, a limited activity spectrum, a paucity of targets, and fungal resistance, all of which continue to be significant issues in developing antifungal drugs. The emergence of antifungal drug resistance has eliminated accessible drug classes as treatment choices, which significantly compromises the clinical management of fungal illnesses. In some situations, the emergence of strains resistant to many antifungal medications is a major concern. Although new medications have been developed to address this issue, antifungal drug resistance has grown more pronounced, particularly in patients who need long-term care or are undergoing antifungal prophylaxis. Moreover, the mechanisms that cause resistance must be well understood, including modifications in drug target affinities and abundances, along with biofilms and efflux pumps that diminish intracellular drug levels, to find novel antifungal drugs and drug targets. In this review, different classes of antifungal agents, and their resistance mechanisms, have been discussed. The latter part of the review focuses on the strategies by which we can overcome this serious issue of antifungal resistance in humans.

Mechanisms of Azole Resistance in CandidaA Narrative Review

Candida species, opportunistic fungal pathogens, pose a significant threat to human health, and the emergence of drug-resistant Candida strains has become a major concern in clinical settings, limiting the efficacy of antifungal therapies. Azoles are a class of antifungal agents that play a crucial role in the management of fungal infections. They have several advantages which contributes to their widespread use, like their broad-spectrum activity, availability in systemic and topical formulations, good oral bioavailability, tolerability, target specificity, established efficacy, and low toxicity for long-term prophylaxis. Azole resistance in Candida species poses a significant therapeutic challenge in the management of fungal infections, particularly in immunocompromised individuals. One common mechanism of resistance involves alterations in the target enzyme, cytochrome P450 14-alpha-demethylase (CYP51), which is essential for ergosterol biosynthesis, a crucial component of fungal cell membranes. Mutations in the CYP51 gene can lead to structural changes in the enzyme, reducing its affinity for azoles and thus decreasing their inhibitory effect. Another mechanism involves overexpression of efflux pumps, such as ATP-binding cassette (ABC) transporters and major facilitator superfamily (MFS) transporters. These pumps actively remove azoles from fungal cells, preventing them from reaching effective concentrations and thereby reducing their antifungal activity. A better understanding of the mechanisms underlying drug resistance is crucial for developing effective strategies to overcome this growing problem. This review describes and summarises the mechanisms associated with azole resistance in Candida, exploring the genetic, biochemical, and cellular factors contributing to this phenomenon. Additionally, potential approaches to combat azole resistance are discussed, aiming to pave the way for the development of novel therapeutic interventions.

Mechanisms of Azole Resistance in CandidaA Narrative Review

Candida species, opportunistic fungal pathogens, pose a significant threat to human health, and the emergence of drug-resistant Candida strains has become a major concern in clinical settings, limiting the efficacy of antifungal therapies. Azoles are a class of antifungal agents that play a crucial role in the management of fungal infections. They have several advantages which contributes to their widespread use, like their broad-spectrum activity, availability in systemic and topical formulations, good oral bioavailability, tolerability, target specificity, established efficacy, and low toxicity for long-term prophylaxis. Azole resistance in Candida species poses a significant therapeutic challenge in the management of fungal infections, particularly in immunocompromised individuals. One common mechanism of resistance involves alterations in the target enzyme, cytochrome P450 14-alpha-demethylase (CYP51), which is essential for ergosterol biosynthesis, a crucial component of fungal cell membranes. Mutations in the CYP51 gene can lead to structural changes in the enzyme, reducing its affinity for azoles and thus decreasing their inhibitory effect. Another mechanism involves overexpression of efflux pumps, such as ATP-binding cassette (ABC) transporters and major facilitator superfamily (MFS) transporters. These pumps actively remove azoles from fungal cells, preventing them from reaching effective concentrations and thereby reducing their antifungal activity. A better understanding of the mechanisms underlying drug resistance is crucial for developing effective strategies to overcome this growing problem. This review describes and summarises the mechanisms associated with azole resistance in Candida, exploring the genetic, biochemical, and cellular factors contributing to this phenomenon. Additionally, potential approaches to combat azole resistance are discussed, aiming to pave the way for the development of novel therapeutic interventions

Phenotypic and Genotypic Characterization of Candida auris, an Emerging Pathogen Isolated from Blood

Introduction:Candida auris has been reported from various health care settings and has recently gained importance because of its intrinsic resistance to many classes of antifungal agents and to disinfection. The outbreak potential and high mortality associated with Candida auris infection reinforces the need for speciation. Routine conventional methods are cumbersome and automated systems are unable to confirm up to species level. Materials and Methods:Candida auris isolates from consecutive non-repetitive blood cultures over a 1-year period were speciated based on phenotypic, physiological and biochemical tests and VITEK. Molecular confirmation was done by PCR-RFLP and MALDI-TOF. Anti- fungal susceptibility test was performed according to CLSI guidelines (2021), using suitable controls. Virulence factors such as production of Hemolysin, Phospholipase, Esterase and Bio-film production were demonstrated. RT-PCR was used to screen the COVID-19 status using SD-Biosensor kit. Baseline data and clinical history were collected and analysed. Results: Of 3632 blood cultures (0.77%), 28 Candida sp. were isolated including 9 Candida auris, (9/28, 32.14%). Of these 8 were from COVID-19 positive patients (88.89%), while 1 was from COVID-19 negative patient (11.11%). Two patients survived, while the remaining 7 patients succumbed to the disease. Conclusion: The increasing incidence of Candidiasis especially during the COVID-19 pandemic has raised the concern for early speciation. Through multi-modal strategies such as quick and correct identification, active surveillance, guided reporting, stringent infection control measures and correct use of anti-fungals through proper susceptibility testing, we can prevent the occurrence and spread of new Candida auris cases in the future.

S1.4b Challenges in diagnosing and management of invasive fungal infections during the pandemic

S1.4 Fungal infections in Asia, bringing it out of the dark, September 21, 2022, 11:00 AM - 12:30 PMInvasive fungal diseases have been increasing in Asian countries. Recent advances in novel medical care such as solid organ and stem cell transplantations, chemotherapy for cancer treatment, and corticosteroid therapy, resulted in the increased prevalence of invasive mycoses. Invasive aspergillosis, mucormycosis, and endemic mycoses are among the most common mold infections in Asia. Non-classical and novel risk factors of invasive fungal diseases have been increasingly recognized in Asia. In contrast to the classical neutropenic patients, most of the patients with invasive mycoses who had non-classical risk factors are mostly non-neutropenic and may present with an atypical clinical manifestation. These novel risk factors include biologic agents or small molecule kinase inhibitors used for cancer treatment, and severe viral pneumonia such as influenza pneumonia or coronavirus disease 2019 (COVID-19) pneumonia. Recently, COVID-19-associated aspergillosis (CAPA) and COVID-19-associated mucormycosis (CAM) have been described. These particular mold infections had high mortality. Treatment of CAPA and CAM are similar to those who had mold infections without COVID-19. However, the interaction between triazole and drugs used for the treatment of COVID-19 must be taken into consideration. Timely and accurate diagnoses are crucial for the management of invasive fungal infections. Conventional fungal cultures from sterile clinical samples or blood are useful but they are time-consuming. Nevertheless, the diagnosis of invasive mold infections is challenging as the imaging is non-specific and the serological tests are not widely available in Asian countries. In some circumstances such as those with non-classical risk factors, serology revealed relatively low sensitivities. Molecular diagnostic tests are also the unmet needs among Asian countries for timely and accurate diagnosis of invasive fungal diseases. Several factors should be considered for the appropriate choice of antifungal agents, including antifungal coverage, adverse effects, underlying conditions, drug-drug interactions, and cost. Recently, novel antifungal agents such as novel triazoles or new classes of antifungal agents have been studied and may be a promising choice for the treatment of invasive fungal diseases.

Candida auris Pan-Drug-Resistant to Four Classes of Antifungal Agents.

Candida auris is an urgent antimicrobial resistance threat due to its global emergence, high mortality, and persistent transmissions. Nearly half of C. auris clinical and surveillance cases in the United States are from the New York and New Jersey Metropolitan area. We performed genome, and drug-resistance analysis of C. auris isolates from a patient who underwent multi-visceral transplantation. Whole-genome comparisons of 19 isolates, collected over 72 days, revealed closed similarity (Average Nucleotide Identity > 0.9996; Aligned Percentage > 0.9764) and a distinct subcluster of NY C. auris South Asia Clade I. All isolates had azole-linked resistance in ERG11(K143R) and CDR1(V704L). Echinocandin resistance first appeared with FKS1(S639Y) mutation and then a unique FKS1(F635C) mutation. Flucytosine-resistant isolates had mutations in FCY1, FUR1, and ADE17. Two pan-drug-resistant C. auris isolates had uracil phosphoribosyltransferase deletion (FUR1[1Δ33]) and the elimination of FUR1 expression, confirmed by a qPCR test developed in this study. Besides ERG11 mutations, four amphotericin B-resistant isolates showed no distinct nonsynonymous variants suggesting unknown genetic elements driving the resistance. Pan-drug-resistant C. auris isolates were not susceptible to two-drug antifungal combinations tested by checkerboard, Etest, and time-kill methods. The fungal population pattern, discerned from SNP phylogenetic analysis, was consistent with in-hospital or inpatient evolution of C. auris isolates circulating locally and not indicative of a recent introduction from elsewhere. The emergence of pan-drug-resistance to four major classes of antifungals in C. auris is alarming. Patients at high risk for drug-resistant C. auris might require novel therapeutic strategies and targeted pre-and/or posttransplant surveillance.

Efficacy of octenidine against emerging echinocandin-, azole- and multidrug-resistant Candida albicans and Candida glabrata

Infections due to Candida species represent a serious threat to healthcare facilities. Only a few classes of antifungal agents are available, and the rapid emergence of (multi)drug resistance eliminates effective treatment options for successful patient outcome. Topically applied antiseptics may represent a suitable tool for infection control and local therapy. This study aimed to investigate the in vitro efficacy of the widely used antiseptic octenidine (OCT) against clinical isolates of emerging azole-, echinocandin- and multi-resistant Candida albicans and Candida glabrata. The antifungal activity of different concentrations of OCT ranging from 0.001% to 0.05% and of OCT-containing ready-to-use products was determined against well-characterised (multidrug) resistant C. albicans and C. glabrata isolates, including susceptible wild-type strains. Quantitative suspension tests were performed under "clean conditions" (0.3 g/L bovine serum albumin) and under "dirty conditions" (3 g/L albumin+3 mL/L defibrinated sheep blood) as well as various contact times (30 s, 1 min, 2 min) according to EN13624:2013. Even in the presence of a high organic load, pure OCT at 0.05% and a contact time of 30 s was fully effective for all Candida strains, with growth kinetics indicating a time- and concentration-dependent activity. Importantly, commercially available OCT-based products achieved the required reduction of ≥4 log10 for all Candida isolates under the most challenging dirty conditions within two minutes, which makes them suitable for routine clinical use. These results encourage consideration of the well-tolerated antiseptic molecule OCT in the eradication of emerging (multidrug) resistant C. albicans and C. glabrata.

Consensus guidelines for the diagnosis and management of invasive aspergillosis, 2021.

Invasive aspergillosis (IA) in haematology/oncology patients presents as primary infection or breakthrough infection, which can become refractory to antifungal treatment and has a high associated mortality. Other emerging patient risk groups include patients in the intensive care setting with severe respiratory viral infections, including COVID-19. These guidelines present key diagnostic and treatment recommendations in light of advances in knowledge since the previous guidelines in 2014. Culture and histological-based methods remain central to the diagnosis of IA. There is increasing evidence for the utility of non-culture methods employing fungal biomarkers in pre-emptive screening for infection, as well as for IA diagnosis when used in combination. Although azole resistance appears to be uncommon in Australia, susceptibility testing of clinical Aspergillus fumigatus complex isolates is recommended. Voriconazole remains the preferred first-line antifungal agent for treating primary IA, including for extrapulmonary disease. Recommendations for paediatric treatment broadly follow those for adults. For breakthrough and refractory IA, a change in class of antifungal agent is strongly recommended, and agents under clinical trial may need to be considered. Newer immunological-based imaging modalities warrant further study, while surveillance for IA and antifungal resistance remain essential to informing the relevance of current treatment recommendations.

Schiff bases of sulphonamides as a new class of antifungal agent against multidrug-resistant Candida auris.

Invasive Candida infections in hospitalized and immunocompromised or critically ill patients have become an important cause of morbidity and mortality. There are increasing reports of multidrug resistance in several Candida species that cause Candidemia, including C. glabrata and C. auris, with limited numbers of antifungal agents available to treat patients with invasive Candida infections. Therefore, there is an urgent need to discover new antifungal agents that work against multidrug‐resistant Candida species, particularly C. auris, which has been identified as an emerging global pathogen. In this article, we report a new class of antifungal agents, the Schiff bases of sulphonamides, that show activity against all Candida species tested, with an MIC range of 4–32 µg/ml. Compound 2b showed activity against C. glabrata and a panel of fluconazole‐resistant C. auris strains, with MICs of 4–16 µg/ml. The drug‐like nature of these Schiff bases offers opportunities to optimize these compounds with medicinal chemistry techniques to obtain more potent analogs that can be progressed toward pre‐clinical evaluation.

Preliminary Characterization of NP339, a Novel Polyarginine Peptide with Broad Antifungal Activity.

ABSTRACTFungi cause disease in nearly one billion individuals worldwide. Only three classes of antifungal agents are currently available in mainstream clinical use. Emerging and drug-resistant fungi, toxicity, and drug-drug interactions compromise their efficacy and applicability. Consequently, new and improved antifungal therapies are urgently needed. In response to that need, we have developed NP339, a 2-kDa polyarginine peptide that is active against pathogenic fungi from the genera Candida, Aspergillus, and Cryptococcus, as well as others. NP339 was designed based on endogenous cationic human defense peptides, which are constituents of the cornerstone of immune defense against pathogenic microbes. NP339 specifically targets the fungal cell membrane through a charge-charge-initiated membrane interaction and therefore possesses a differentiated safety and toxicity profile to existing antifungal classes. NP339 is rapidly fungicidal and does not elicit resistance in target fungi upon extensive passaging in vitro. Preliminary analyses in murine models indicate scope for therapeutic application of NP339 against a range of systemic and mucocutaneous fungal infections. Collectively, these data indicate that NP339 can be developed into a highly differentiated, first-in-class antifungal candidate for poorly served invasive and other serious fungal diseases.

The Future of Antifungal Drug Therapy: Novel Compounds and Targets.

Fungal infections are a universal problem and are routinely associated with high morbidity and mortality rates in immunocompromised patients. Existing therapies comprise five different classes of antifungal agents, four of which target the synthesis of ergosterol and cell wall glucans. However, the currently available antifungals have many limitations, including poor oral bioavailability, narrow therapeutic indices, and emerging drug resistance resulting from their use, thus making it essential to investigate the development of novel drugs which can overcome these limitations and add to the antifungal armamentarium. Advances have been made in antifungal drug discovery research and development over the past few years as evidenced by the presence of several new compounds currently in various stages of development. In the following minireview, we provide a comprehensive summary of compounds aimed at one or more novel molecular targets. We also briefly describe potential pathways relevant for fungal pathogenesis that can be considered for drug development in the near future.

Manogepix (APX001A) In Vitro Activity against Candida auris: Head-to-Head Comparison of EUCAST and CLSI MICs.

Fosmanogepix is a novel prodrug in a new class of antifungal agents. Manogepix is the active moiety. We evaluated the CLSI and EUCAST MICs of manogepix and eight comparators against Candida auris CLSI M27-A3 susceptibility testing of manogepix was performed for 122 C. auris isolates and compared to CLSI and EUCAST MICs for manogepix and eight comparators. Differences and agreement were calculated for each compound. Wild-type upper limits (WT-ULs; the upper MIC where the wild-type distribution ends) for manogepix and correlations with other drugs' MICs were determined. Manogepix MICs (CLSI/EUCAST [mg/liter]) and WT-ULs were as follows: MIC50s, 0.008/0.016; MIC90s, 0.03/0.03; ranges, 0.001 to 0.25/0.001 to 0.125; 97.5% and 99% WT-ULs, 0.03/0.125 and 0.06/0.125, respectively. The manogepix CLSI/EUCAST MIC distributions spanned 9/8 dilutions, respectively. Significant correlation was found for all azoles, particularly fluconazole (r = 0.22 to 0.74, P < 0.05). Isolates with EUCAST manogepix MICs of ≤0.004 had 7.6-/10.2-fold-lower fluconazole CLSI/EUCAST MICs than the remaining isolates that had higher manogepix MICs. The highest essential agreement between CLSI and EUCAST results was observed for manogepix and fluconazole, with a median difference of -1 to 0 2-fold dilutions, 90th percentile absolute difference of 1, and 90 to 92% and 98 to 100% agreement within ±1 and ±2 dilutions. The lowest agreements within ±1 and ±2 dilutions were found for isavuconazole and anidulafungin (44 to 50% and 69 to 76%). The correlation between CLSI and EUCAST manogepix MICs against C. auris was excellent. Differential MICs were found, and these correlated with fluconazole MICs, suggesting that the C. auris population is a mix of wild-type isolates and non-wild-type isolates with low-grade manogepix MIC elevation, probably involving efflux pump expression. However, manogepix was the most potent agent against C. auris in this in vitro study.

Oral Ibrexafungerp: an investigational agent for the treatment of vulvovaginal candidiasis

ABSTRACT Introduction Vulvovaginal candidiasis (VVC) is a common fungal infection caused by predominantly Candida albicans, and is diagnosed in up to 40% of women with vaginal complaints in the primary care setting. Approximately 75% of women experience at least one episode during their reproductive years. Areas covered Ibrexafungerp is an orally active, semi-synthetic triterpenoid glucan synthase inhibitor under development for treatment and prevention of VVC. We present the chemistry, mechanism of action, pharmacology, microbiology, and results from clinical studies with ibrexafungerp in women with VVC. Expert opinion Ibrexafungerp addresses several unmet needs with existing antifungal drugs as a first in a new class of antifungal agents with a novel mechanism of action demonstrating no antifungal cross resistance with azoles, and fungicidal activity against Candida spp., including fluconazole-resistant species. Some of the key attributes of ibrexafungerp related to VVC include oral one-day dosing, high tissue penetration, enhanced activity at low pH seen in the vagina, low risk for clinically significant drug–drug interactions, and a low risk of adverse events. If approved, ibrexafungerp will be the first new antifungal agent available for the treatment of VVC in more than 20 years and the only oral, non-azole antifungal approved for women suffering from VVC.

Targeting adhesion in fungal pathogen Candida albicans.

Fungal infections with increasing resistance to conventional therapies are a growing concern. Candida albicans is a major opportunistic yeast responsible for mucosal and invasive infections. Targeting the initial step of the infection process (i.e., C. albicans adhesion to the host cell) is a promising strategy. A wide variety of molecules can interfere with adhesion processes via an assortment of mechanisms. Herein, we focus on how small molecules disrupt biosynthesis of fungal cell wall components and membrane structure, prevent the localization of GPI-anchor proteins, inhibit production of enzymes involved in adhesion, downregulate genes encoding adhesins and competitively inhibit receptor interactions. As a result, adhesion of C. albicans to host cells is reduced, paving the way to new classes of antifungal agents.

Effects of Some Ethno Medicinal Plant Extracts on Botryodiplodia theobromae the Causal Organism of Yam (Dioscorea rotundata Poir) Rot

Post-harvest deterioration and rot caused by diverse microorganisms is the single most important factor militating against yam production in Nigeria. In an approach towards the development of ecofriendly antifungal compound in controlling yam rot, ethanol and aqueous extracts of six commonly available plants: Vernonia amygdalina, Ocimum gratissimum, Azadirachta indica, Cymbopogon citratus, Carica papaya and Citrus sinensis were tested in combination for their synergistic effect against Botryodiplodia theobromae. Four different extract concentrations (2.5%, 5.0%, 7.5% and 10%) were obtained from each extract mixture. Cold solvent extraction method was used for the extraction of plant materials while food poisoning technique was used for in vitro screening of plant extracts against rot inducing fungal organism. Botryodiplodia theobromae was tested to be pathogenic on healthy yam tubers with rot incidence of 80 mm. The synergistic effects of the combined extract varied with the plants combined, solvent of extraction, concentration of extract and test fungi. Ethanol extract showed greater effect in the inhibition of the entire organism than aqueous. All the extract combinations that had Neem as a component did better than other combinations in aqueous extracts. Inhibition of fungal growth was best observed at 7.5% and 10% extract concentrations. The highest inhibitory effect on the test organism (Botryodiplodia theobromae) was by the combination of Neem/Bitter leaf and Orange/Scent leaf, with values of 98.40±0.095% and 94.24±0.583% respectively for aqueous while the highest inhibition for ethanol extract was observed from Scent leaf/Bitter leaf and Pawpaw/Lemon, with values of 99.80±0.000% and 98.83±0.619% respectively these were significantly (P&lt;0.05) better than other combinations. With respect to the synergistic activity between the plants materials combined in this study, all the combinations showed great synergism against the test organisms. This is likely to be a means of achieving pragmatic, effective control and prevention of food spoilage, since the development of new classes of antifungal agents is of paramount importance. The crude aqueous and ethanolic extracts of all the six plant extracts showed potential synergy on organisms responsible for yam rot, hence they are recommended for the control of rot inducing microbial organisms.