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This research focused on the synthesis and analysis of two novel Ru(II)-based complexes, cis-[RuCl(Hind)(phen)2]PF6 (FOR022) and cis-[Ru(Hind)2(phen)2](PF6)2 (FOR0E2), where Hind represents indazole and phen stands for 1,10-phenanthroline. These compounds were thoroughly characterized using various methods such as elemental analysis, spectroscopy techniques, and electrochemistry assay, confirming their structures. The research highlights the effectiveness of the compound FOR0E2 in exhibiting strong cytotoxic properties against various tumor cell lines, including HCT116, HepG2, HL-60, LNcaP, and PC-3, with half-maximal inhibitory concentration (IC50) values ranging from 10.7 to 25.2 μmol L−1. Additionally, FOR0E2 showed substantial leishmanicidal capabilities against both the promastigote and amastigote forms of L. amazonensis, with IC50 values of 5.7 μmol L−1 and 1.6 μmol L−1, respectively. These outcomes suggest that the inclusion of indazole in FOR022 and FOR0E2 significantly enhances their biological effectiveness, positioning it as a promising candidate for pharmacological treatments. [ABSTRACT FROM AUTHOR]

Zwitterionic compounds are an emergent class of energetic materials and have gained synthetic interest of many in the recent years. Due to their better packing efficiencies and strong inter/intramolecular electrostatic interactions, they often ensue superior energetic properties than their salt analogues. A systematic review from the perspective of design, synthesis, and physicochemical properties evaluation of the zwitterionic energetic materials is presented. Depending on the parent ring(s) used for the synthesis and the type of moieties bearing positive and negative charges, different classes of energetic materials, such as primary explosives, secondary explosives, heat resistant explosives, oxidizers, etc., may result. The properties of some of the energetic zwitterionic compounds are also compared with analogous energetic salts. This review will encourage readers to explore the possibility of designing new zwitterionic energetic materials. [ABSTRACT FROM AUTHOR]

Invasive fungal infections are rapidly increasing, and the opportunistic pathogenic Candida species are the fourth most common cause of nosocomial systemic infections. The current antifungal classes, of which azoles are the most widely used, all have shortcomings. Azoles are generally considered fungistatic rather than fungicidal, they do not actively kill fungal cells and therefore resistance against azoles can be rapidly acquired. Combination therapies with azoles provide an interesting therapeutic outlook and agents limiting iron are excellent candidates. We summarize how iron is acquired by the host and transported towards both storage and iron‐utilizing organelles. We indicate whether these pathways alter azole susceptibility and/or tolerance, to finally link these transport mechanisms to mitochondrial iron availability. In this review, we highlight putative novel intracellular iron shuffling mechanisms and indicate that mitochondrial iron dynamics in relation to azole treatment and iron limitation is a significant knowledge gap. [ABSTRACT FROM AUTHOR]

Background Objective Methods Results Conclusion Nakaseomyces glabratus (N. glabratus) formerly known as Candida glabrata (C. glabrata), is an endogenous opportunistic pathogen, which is generally located in the gastrointestinal tract but can spread in immunocompromised patients. N. glabratus is the second most common pathogen that causes candidemia in several countries. N. glabratus virulence factors may increase antifungal resistance and reduce the number of available treatment options. High resistance to azoles and increasing resistance to echinocandins have been previously reported in N. glabratus.To establish the distribution of N. glabratus isolates in Europe and its drug susceptibility/resistance in each country over the last 7 years.The search was performed across three databases: PubMed, Scopus and Scielo, using the MeSH terms: “Candida glabrata”, “Nakaseomyces glabratus”, “Europe”, “resistance” and “Epidemiology” exclusively in English. All available information from January 2002 to December 2022 was included, excluding reviews, meta‐analyses and book chapters.Fifty‐seven articles with information on antifungal susceptibility in Europe were retrieved and analysed with a total of 15,400 reported C. glabrata isolates. Remarkably, nations that presented the maximum number of cases during the study period included the United Kingdom (n = 7241, 47.02%), France (n = 3190, 20.71%), Spain (n = 900, 5.84%), Hungary (n = 745, 4.84%) and Italy (n = 486, 3.16%). C. glabrata isolates presented resistance to azoles [voriconazole (n = 2225, 14.45%), fluconazole (n = 1612, 10.47%), itraconazole (n = 337, 2.19%) and clotrimazole (n = 89, 0.58%)], increased resistance to echinocandins, especially to anidulafungin (n = 138, 0.89%), and high sensitivity to amphotericin B.The number of candidemia cases associated with triazole‐resistant N. glabratus isolates have been increasing in Europe. Therefore, echinocandins and amphotericin B can be considered optional empirical treatments; however, antifungal susceptibility testing is required to determine the best therapeutic options. [ABSTRACT FROM AUTHOR]

The reactivity of imidazole, pyrazole, 1,2,4‐triazole, 1,2,3‐triazole, and tetrazole with acetone (propan‐2‐one) has been studied by 1H and 13C NMR using acetone‐d6 as solvent at temperatures ranging from 173 to 300 K at 10 K intervals. Simultaneously, the reaction has been theoretically calculated at the B3LYP/6‐311++G(d,p) level, and experimental and theoretical results have been compared. The equilibrium constants between azoles and adducts α,α‐dimethyl‐azole‐methanol were analyzed, assuming that the straight part of the plots –R ln Ke vs. 1/T can be used to determine ΔH and ΔS. Calculated and experimental data are related, but the theoretical values are proportionally higher. The tautomerism of triazoles and tetrazole has been considered in order to discuss the reactions. [ABSTRACT FROM AUTHOR]

Plenodomus lingam (Leptosphaeria maculans) and P. biglobosus (L. biglobosa) are fungi causing Phoma leaf spot/stem canker, an international damaging disease of oilseed rape (Brassica napus) and other brassicas. In Europe, fungicides used for disease management are mainly sterol 14α‐demethylase (CYP51) inhibitors (DMIs/azoles); quinone‐outside inhibitors (QoIs) and succinate dehydrogenase inhibitors (SDHIs) are also used. Decreased DMI sensitivity has emerged in Australian and eastern European P. lingam populations and is mediated by CYP51 promoter inserts resulting in target site overexpression. In this study using in vitro sensitivity testing, we report decreased DMI (prothioconazole‐desthio, mefentrifluconazole) sensitivity in modern western European P. lingam isolates (collected 2022–2023) compared to older baseline (1992–2005) isolates. Around 85% of modern western European P. lingam isolates collected, for which the CYP51 promoter region was sequenced, carried a promoter insert, but target site alterations were not detected. Six different CYP51 promoter inserts were identified, most commonly a 237 bp fragment of the Sahana transposable element. Inserts were associated with an approximately 3‐ to 10‐fold decrease in sensitivity to the DMIs tested. In contrast to P. lingam, PCR screening revealed CYP51 promoter inserts were absent in modern western European P. biglobosus isolates (2021–2023). Combined data indicate P. lingam isolates lacking an insert were similarly (or slightly more) sensitive to the DMIs tested for P. biglobosus, whereas those carrying an insert were slightly less sensitive than P. biglobosus. No evidence for substantive sensitivity shifts to the QoI (pyraclostrobin) or SDHI (boscalid) fungicides tested was obtained for either Plenodomus species. [ABSTRACT FROM AUTHOR]

Antimicrobial resistance poses a major threat to global health as the number of efficient antimicrobials decreases and the number of resistant pathogens rises. Our research group has been actively involved in the design of novel antimicrobial drugs. The blueprints of these compounds were azolic heterocycles, particularly thiazole. Starting with oxadiazolines, our research group explored, one by one, the other five-membered heterocycles, developing more or less potent compounds. An overview of this research activity conducted by our research group allowed us to observe an evolution in the methodology used (from inhibition zone diameters to minimal inhibitory concentrations and antibiofilm potential determination) correlated with the design of azole compounds based on results obtained from molecular modeling. The purpose of this review is to present the development of in-house azole compounds with antimicrobial activity, designed over the years by this research group from the departments of Pharmaceutical and Therapeutical Chemistry in Cluj-Napoca. [ABSTRACT FROM AUTHOR]

Fungal resistance is a public health concern due to the limited availability of antifungal resources and the complexities associated with treating persistent fungal infections. Azoles are thus far the primary line of defense against fungi. Specifically, azoles inhibit the conversion of lanosterol to ergosterol, producing defective sterols and impairing fluidity in fungal plasmatic membranes. Studies on azole resistance have emphasized specific point mutations in CYP51/ERG11 proteins linked to resistance. Although very insightful, the traditional approach to studying azole resistance is time-consuming and prone to errors during meticulous alignment evaluation. It relies on a reference-based method using a specific protein sequence obtained from a wild-type (WT) phenotype. Therefore, this study introduces a machine learning (ML)-based approach utilizing molecular descriptors representing the physiochemical attributes of CYP51/ERG11 protein isoforms. This approach aims to unravel hidden patterns associated with azole resistance. The results highlight that descriptors related to amino acid composition and their combination of hydrophobicity and hydrophilicity effectively explain the slight differences between the resistant non-wild-type (NWT) and WT (nonresistant) protein sequences. This study underscores the potential of ML to unravel nuanced patterns in CYP51/ERG11 sequences, providing valuable molecular signatures that could inform future endeavors in drug development and computational screening of resistant and nonresistant fungal lineages. [ABSTRACT FROM AUTHOR]

Azole antifungals inhibit the sterol C14-demethylase (CYP51/Erg11) of the ergosterol biosynthesis pathway. Here we show that the azole-induced synthesis of fungicidal cell wall carbohydrate patches in the pathogenic mold Aspergillus fumigatus strictly correlates with the accumulation of the CYP51 substrate eburicol. A lack of other essential ergosterol biosynthesis enzymes, such as sterol C24-methyltransferase (Erg6A), squalene synthase (Erg9) or squalene epoxidase (Erg1) does not trigger comparable cell wall alterations. Partial repression of Erg6A, which converts lanosterol into eburicol, increases azole resistance. The sterol C5-desaturase (ERG3)-dependent conversion of eburicol into 14-methylergosta-8,24(28)-dien-3β,6α-diol, the "toxic diol" responsible for the fungistatic activity against yeasts, is not required for the fungicidal effects in A. fumigatus. While ERG3-lacking yeasts are azole resistant, ERG3-lacking A. fumigatus becomes more susceptible. Mutants lacking mitochondrial complex III functionality, which are much less effectively killed, but strongly inhibited in growth by azoles, convert eburicol more efficiently into the supposedly "toxic diol". We propose that the mode of action of azoles against A. fumigatus relies on accumulation of eburicol which exerts fungicidal effects by triggering cell wall carbohydrate patch formation. Azole antifungals inhibit the ergosterol biosynthesis enzyme CYP51, but their effects on fungal viability and growth vary greatly among fungal species. Here, the authors provide evidence that the mode of action of azoles against Aspergillus fumigatus relies on accumulation of the CYP51 substrate eburicol, which exerts fungicidal effects by triggering cell-wall carbohydrate patch formation. [ABSTRACT FROM AUTHOR]

N,N‐dialkylbenzofuran‐ and N,N‐dialkylbenzothiophene‐2‐carboxamides were readily prepared from bare benzofuran and benzothiophene by deprotocupration followed by trapping with N,N‐dialkylcarbamoyl chlorides. They were reacted with 2‐benzofuryl‐ and 2‐benzothienyllithiums to form symmetrical and unsymmetrical diarylketones, or underwent deprotolithiation‐electrophilic trapping sequences at their 3 position. From 3‐iodinated derivatives, copper‐catalysed N‐arylation of azoles was performed, followed by lithium amide‐promoted cyclisation, to give 'tripentone' analogues. The diarylketones were also iodinated at their 3,3' positions and then engaged in the copper‐promoted double N‐arylation of anilines, giving rise to a family of original pentacyclic derivatives. A preliminary assessment of their electrochemical and biological properties was carried out, showing promising results against the proliferation of melanoma cells. [ABSTRACT FROM AUTHOR]

Background: The resistance of Aspergillus flavus to the azole antifungal drugs is an emerging problem. Mutations in the molecular targets of the azole antifungals ‐ CYP 51 A, B and C ‐ are possible mechanisms of resistance, but data to confirm this hypothesis are scarce. In addition, the behaviour of resistant strains in vitro and in vivo is not yet understood. Objectives: This study had 3 objectives. The first was to compare the sequences of CYP51 A, B and C in resistant and susceptible strains of A. flavus. The second was to look for the existence of a fitness cost associated with resistance. The third was to evaluate the activity of voriconazole and posaconazole on resistant strains in the Galleria mellonella model. Methods: The CYP51 A, B and C sequences of seven resistant strains with those of four susceptible strains are compared. Fitness costs were assessed by growing the strains in RPMI medium and testing their virulence in G. mellonella larvae. In addition, G. mellonella larvae infected with strains of A. flavus were treated with voriconazole and posaconazole. Results: In the CYP51A sequences, we found the A91T, C708T and A1296T nucleotide substitutions only in the resistant strains. The resistant strains showed a fitness cost with reduced in vitro growth and reduced virulence in G. mellonella. In vivo resistance to posaconazole is confirmed in a strain with the highest MIC for this antifungal agent. Conclusions: These results allow to conclude that some substitutions in CYP51 genes, in particular CYP51A, contribute to resistance to azole drugs in A. flavus. The study of the relationship between drug dosage and treatment duration with resistance and the reduction of fitness costs in resistant strains is a major perspective of this study. This work could help to establish recommendations for the treatment of infections with resistant strains of A. flavus. [ABSTRACT FROM AUTHOR]

Background: Candida vulturna is an emerging pathogen belonging to the Metshnikowiaceae family together with Candida auris and Candida haemulonii species complex. Some strains of this species were reported to be resistant to several antifungal agents. Objectives: This study aims to address identification difficulties, evaluate antiungal susceptibilities and explore the molecular mechanisms of azole resistance of Candida vulturna. Methods: We studied five C. vulturna clinical strains isolated in three Colombian cities. Identification was performed by phenotypical, proteomic and molecular methods. Antifungal susceptibility testing was performed following CLSI protocol. Its ERG11 genes were sequenced and a substitution was encountered in azole resistant isolates. To confirm the role of this substitution in the resistance phenotype, Saccharomyces cerevisiae strains with a chimeric ERG11 gene were created. Results: Discrepancies in identification methods are highlighted. Sequencing confirmed the identification as C. vulturna. Antifungal susceptibility varied among strains, with four strains exhibiting reduced susceptibility to azoles and amphotericin B. ERG11 sequencing showed a point mutation (producing a P135S substitution) that was associated with the azole‐resistant phenotype. Conclusions: This study contributes to the understanding of C. vulturna's identification challenges, its susceptibility patterns, and sheds light on its molecular mechanisms of azole resistance. [ABSTRACT FROM AUTHOR]

The medicinal chemistry of ferrocene has gained its momentum after the discovery of biological activities of ferrocifen and ferroquine. These ferrocenyl drugs have been designed by replacing the aromatic moiety of the organic drugs, tamoxifen and chloroquine respectively, with a ferrocenyl unit. The promising biological activities of these ferrocenyl drugs have paved a path to explore the medicinal applications of several ferrocenyl conjugates. In these conjugates, the ferrocenyl moiety has played a vital role in enhancing or imparting the anticancer activity to the molecule. The ferrocenyl conjugates induce the cytotoxicity by generating reactive oxygen species and thereby damaging the DNA. In medicinal chemistry, the five membered nitrogen heterocycles (azoles) play a significant role due to their rigid ring structure and hydrogen bonding ability with the biomolecules. Several potent drug candidates with azole groups have been in use as chemotherapeutics. Considering the importance of ferrocenyl moiety and azole groups, several ferrocenyl azole conjugates have been synthesized and screened for their biological activities. Hence, in the view of a wide scope in the development of potent drugs based on ferrocenyl azole conjugates, herein we present the details of synthesis and the anticancer activities of ferrocenyl compounds bearing azole groups such as imidazole, triazoles, thiazole and isoxazoles. [ABSTRACT FROM AUTHOR]

Objectives: This study evaluated the role of Upc2 in the development of azole resistance in Candida albicans isolates from Lebanese hospitalized patients and determined a correlation between resistance and virulence. Methods: The UPC2 gene which codes for an ergosterol biosynthesis regulator was sequenced and analysed in two azole-resistant and one azole-susceptible C. albicans isolates. An amino acid substitution screening was carried out on Upc2 with a focus on its ligand binding domain (LBD) known to interact with ergosterol. Then, Upc2 protein secondary structure prediction and homology modelling were conducted, followed by total plasma membrane ergosterol and cell wall chitin quantifications. For virulence, mouse models of systemic infection were generated and an agar adhesion and invasion test was performed. Results: Azole-resistant isolates harboured novel amino acid substitutions in the LBD of Upc2 and changes in protein secondary structures were observed. In addition, these isolates exhibited a significant increase in plasma membrane ergosterol content. Resistance and virulence were inversely correlated while increased cell wall chitin concentration does not seem to be linked to resistance since even though we observed an increase in chitin concentration, it was not statistically significant. Conclusions: The azole-resistant C. albicans isolates harboured novel amino acid substitutions in the LBD of Upc2 which are speculated to induce an increase in plasma membrane ergosterol content, preventing the binding of azoles to their target, resulting in resistance.

From the standpoint of chemical structures, the organic backbones of energetic materials can be classified into aromatic rings, nonaromatic rings, and open chains. Although the category of aromatic energetic compounds exhibits several advantages in the regulation of energetic properties, the nonaromatic heterocycles, assembling nitramino explosophores with simple alkyl bridges, still have prevailed in benchmark materials. The methylene bridge plays a pivotal role in the constructions of the classic nonaromatic heterocycle-based energetic compounds, e.g., hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX) and octahydro-1,3,5,7-tetranitro-1,3,5,7-tetrazocine (HMX), whereas ethylene bridge is the core moiety of state-of-the-art explosive 2,4,6,8,10,12-hexanitro-2,4,6,8,10,12-hexaazaisowurtzitane (CL-20). In this context, it is of great interest to employ simple and practical bridges to assemble aromatic and nonaromatic nitrogen-rich heterocycles, thereby expanding the structural diversity of energetic materials, e.g., bridged and fused nitrogen-rich poly-heterocycles. Furthermore, alkyl-bridged poly-heterocycles highlight the potential for the open chain type of energetic materials. In this review, the development of alkyl bridges in linking nitrogen-rich heterocycles is presented, and the perspective of the newly constructed energetic backbones is summarized for the future design of advanced energetic materials.

A stereoselective N-alkenylation of azoles with alkynes and iodine(III) electrophile is reported. The reaction between various azoles and internal alkynes is mediated by benziodoxole triflate as the electrophile in a trans-fashion, affording azole-bearing vinylbenziodoxoles in moderate to good yields. The tolerable azole nuclei include pyrazole, indazole, 1,2,3-triazole, benzotriazole, and tetrazole. The iodanyl group in the product can be leveraged as a versatile synthetic handle, allowing for the preparation of hitherto inaccessible types of densely functionalized N-vinylazoles.

In the realm of energetic materials research, there has been notable interest in energetic coordination compounds (ECCs) owing to their remarkable thermal stability and resistance to mechanical stimuli. This study successfully demonstrated the synthesis of an azole-based C–C bonded ECC1 under ambient conditions. A comprehensive characterization study, employing techniques such as IR, TGA-DSC, NMR and single-crystal X-ray diffraction analysis, was conducted. The bulk compound was investigated by PXRD analysis. In-depth exploration of its physicochemical and energetic performance revealed good detonation properties such as a detonation velocity (VOD) of 8553 m s−1 and a detonation pressure (DP) of 36.2 GPa, which surpass those of heat resistant explosives HNS and TATB. Due to its remarkable high melting and onset decomposition temperature (278/379 °C), it also outperforms the benchmark explosive HMX (279 °C) and the heat-resistant explosive HNS (318 °C) and shows a high impact sensitivity (IS) of 20 J and friction sensitivity (FS) of 360 N. The study also employed Hirshfeld surface and 2D fingerprint analysis to elucidate the close contact of atoms within the molecules. The combination of high detonation properties, thermal stability, and low sensitivity makes the synthesized ECC1 intriguing for further investigations and suggests its potential applications as a safe and high-energy-dense material. [ABSTRACT FROM AUTHOR]

Treatment of 2-methylsulfinylbenzazoles with triflic anhydride in the presence of phenols yields the corresponding 4-(p-hydroxyphenyl)-2-methylsulfanylbenzazoles. This regioselective dehydrative C–H/C–H coupling arylation represents a rare example of functionalizations on the benzene rings of benzo-fused azoles. [ABSTRACT FROM AUTHOR]

Introduction: Fungal diseases are frequently associated with elevated mortality rates in elasmobranchs. Currently, there is a notable absence of scientifically validated therapeutic medications that can ensure both effectiveness and safety when administered to this group of animals. The empirical prescription of azole antifungal agents, particularly voriconazole, has been posited as a potentially efficacious treatment approach for addressing most common mycoses in sharks and rays. However, there are still no published pharmacokinetic studies supporting its use in elasmobranchs and there is a lack of scientific base for its utilization in elasmobranchs. Methods: For this study, voriconazole was administered intravenously (IV) and intramuscularly (IM), at a single dose of 4 mg/kg to six adult undulate skates (Raja undulata). A washout period of 8 weeks was left between each route of administration. Blood samples were collected both before and at ten predetermined intervals after each dosing (0.25, 0.5, 1, 1.5, 2, 4, 8, 12, 24, and 36 h after drug administration). Plasma concentrations were quantified using a validated high-performance liquid chromatography method, and pharmacokinetic (PK) data was analyzed through non-compartmental methods. Results: The mean extrapolated concentration at 0 h (C0) after IV administration was 27.19 ± 7.15 µg/mL and the mean peak plasma concentrations (Cmax) ± SEM after IM administration resulted 2.98 ± 0.28 µg/mL at a mean time to maximum concentration (T max) of 1.33 ± 0.17 h. Terminal half-lives were calculated and resulted 11.18 ± 1.32 h for IV injections and 9.59 ± 1.38 h for IM injections. The area under the curve extrapolated to infinity was determined as 58.14 ± 2.79 h·µg/ml following IV injections and 37.60 ± 6.67 h·µg/ml following IM injections. The IM-administered voriconazole exhibited a mean absolute bioavailability of 64.67 ± 11.47%. Discussion: These discoveries provide backing for the possible application of voriconazole through the intramuscular route in undulate skates and support using lower dosage regimens compared to those required for oral administration, emphasizing the importance of conducting further pharmacokinetic studies with antifungals in elasmobranchs. [ABSTRACT FROM AUTHOR]

Herein, a series of novel ferrocenyl/phenyl/thiophenyl‐azoles was disclosed by vinylic amination of ferrocenyl/phenyl/thiophenyl substituted β‐chloro cinnamaldehydes and acrylonitriles. A highly economical and robust chalcogen‐stabilized iron selenide carbonyl cluster Fe3Se2(CO)9 worked as an efficient catalyst under aerobic conditions. The amination of ferrocenyl/phenyl/thiophenyl substituted β‐chloro‐vinylic Csp2‐Cl with azole derivatives was fully established and fabrication of the Csp2‐N bond was completely supported by various spectral analysis. Moreover, wide range of substrates with functionally different azoles were investigated for the present reaction and good to excellent transformation was recorded. Some of the selected ferrocenated azole derivatives were screened for anti‐cancer activity against the prostate cancer cells (PC‐3) and found to be highly active at low concentration of 5.77 μM with IC50 value. Furthermore, HOMO and LUMO levels and energy gap of some selected compounds were calculated by the density functional theory (DFT). [ABSTRACT FROM AUTHOR]

Background: The prevalence of Candida glabrata healthcare‐associated infections is on the rise worldwide and in Lebanon, Candida glabrata infections are difficult to treat as a result of their resistance to azole antifungals and their ability to form biofilms. Objectives: The first objective of this study was to quantify biofilm biomass in the most virulent C. glabrata isolates detected in a Lebanese hospital. In addition, other pathogenicity attributes were evaluated. The second objective was to identify the mechanisms of azole resistance in those isolates. Methods: A mouse model of disseminated systemic infection was developed to evaluate the degree of virulence of 41 azole‐resistant C. glabrata collected from a Lebanese hospital. The most virulent isolates were further evaluated alongside an isolate having attenuated virulence and a reference strain for comparative purposes. A DNA‐sequencing approach was adopted to detect single nucleotide polymorphisms (SNPs) leading to amino acid changes in proteins involved in azole resistance and biofilm formation. This genomic approach was supported by several phenotypic assays. Results: All chosen virulent isolates exhibited increased adhesion and biofilm biomass compared to the isolate having attenuated virulence. The amino acid substitutions D679E and I739N detected in the subtelomeric silencer Sir3 are potentially involved— in increased adhesion. In all isolates, amino acid substitutions were detected in the ATP‐binding cassette transporters Cdr1 and Pdh1 and their transcriptional regulator Pdr1. Conclusions: In summary, increased adhesion led to stable biofilm formation since mutated Sir3 could de‐repress adhesins, while decreased azole susceptibility could result from mutations in Cdr1, Pdh1 and Pdr1. [ABSTRACT FROM AUTHOR]

A series of hybrid compounds with triazole and thiazolidine nuclei connected by a linker has been synthesized and extensively studied. Various synthetic methods for the target compounds have been tested. A microbiological assessment of the obtained compounds was carried out on strains of pathogenic fungi C. albicans, C. non-albicans, multidrug-resistant C. auris, Rhizopus arrhizus, Aspergillus spp. and some dermatophytes and other yeasts. The lowest obtained MIC values for target compounds lie between 0.003 µg/mL and 0.5 µg/mL and therefore the compounds are not inferior or several times better than commercial azole drugs. The length of the acylpiperazine linker has a limited effect on antifungal activity. Some bioisosteric analogues were tested in microbiological analysis, but turned out to be weaker than the leader in activity. The highest activity was demonstrated by a compound with para-chlorobenzylidene substituent in the thiazolidine fragment. Molecular modelling was used to predict binding modes of synthesized molecules and rationalize experimentally observed SAR. The leader compound is twice more effective in inhibiting the formation of germ tubes by Candida albicans yeast cells compared to voriconazole. An increased level of Pdr5, an azoles drug efflux pump was observed, but the increase is lower than that caused by azoles. The results can be useful for further development of more powerful and safe antifungal agents. [ABSTRACT FROM AUTHOR]

Organic azides are universally important in many areas of chemistry, particularly in organic synthesis. The availability of these azides often depends on specific transfer reagents and reaction conditions, or only work with certain substrates. Customizable transfer reagents offer a safe and direct pathway to desired compounds, thereby increasing the availability of N‐alkyl‐azides. In an effort to streamline the synthesis and broaden the scope of N‐azidoethyl‐containing molecules, three different versatile azidoethyl transfer reagents were synthesized and a uniform reaction protocol with azoles as substrates, including imidazole, pyrazole, 1,2,3‐triazole, 1,2,4‐triazole, and tetrazole was established. The resulting azidoethyl‐azoles were further used as ligands for energetic coordination compounds in an effort to create new lead‐free primary explosives. A comprehensive characterization of the transfer reagents, the azidoethyl‐containing products, and energetic coordination compounds was conducted using multinuclear nuclear magnetic resonance (NMR), elemental analysis, mass spectrometry, and infrared spectroscopy (IR). Furthermore, their thermal stability and sensitivity toward friction and impact were determined as well as the detonation properties were calculated by using the EXPLO5 code. [ABSTRACT FROM AUTHOR]

Two new zinc azole complexes incorporated Strandberg-type cluster-based solids, namely (Hpz)6{Zn(pz)4(H2O)2}[{Zn(pz)2P2Mo5O23}2]·8H2O (1) and (Himi)4{Zn(imi)3P2Mo5O23}·7H2O (2) were crystallized using isomeric azole ligands, i.e., pyrazole (pz) and imidazole (imi), respectively. While solid 1 crystallized in triclinic system with space group P-1 with cell parameters a = 9.5647(15), b = 12.558(2), c = 20.340(3) Å, α = 75.907(7), β = 84.727(6), γ = 87.525(7)°, Z = 1; 2 crystallized in orthorhombic system with space group P212121 having cell parameters a = 12.048(3), b = 19.561(5), c = 20.732(5) Å, Z = 4. Both pyrazole and imidazole can form a complex with zinc centres to form an extended solid in 1 and a derivatized Strandberg-type cluster in 2. Interestingly, 1 is a new supramolecular isomer of previously reported solid viz., (pz)[{Zn(pz)3}3{P2Mo5O23}]·2H2O and 2 is the only example wherein a zinc imidazole complex has derivatized a Strandberg-type cluster. Detailed structure analysis of 1 and 2 was carried out, and the role of tectons in dictating the self-assembly of these solids was evaluated. In addition, a solid-state photoluminescence study was carried out for 1 and 2 at room temperature. Two zinc azole complexes incorporated Strandberg-type cluster-based solids and have been crystallized. While 1 is a new supramolecular isomer of (pz)[{Zn(pz)3}3{P2Mo5O23}]·2H2O; 2 is the only example wherein a zinc imidazole complex has derivatized a Strandberg-type cluster. Apart from detailed structural analysis, solid-state photoluminescence of solids has also been investigated. [ABSTRACT FROM AUTHOR]

Microbial contamination poses a threat to both the preservation of library and archival collections and the health of staff and users. This study investigated the microbial communities and potential health risks associated with the UNESCO-classified Norwegian Sea Trade Archive (NST Archive) collection exhibiting visible microbial colonization and staff health concerns. Dust samples from book surfaces and the storage environment were analysed using culturing methods, qPCR, Next Generation Sequencing, and mycotoxin, cytotoxicity, and azole resistance assays. Penicillium sp., Aspergillus sp., and Cladosporium sp. were the most common fungi identified, with some potentially toxic species like Stachybotrys sp., Toxicladosporium sp., and Aspergillus section Fumigati. Fungal resistance to azoles was not detected. Only one mycotoxin, sterigmatocystin, was found in a heavily contaminated book. Dust extracts from books exhibited moderate to high cytotoxicity on human lung cells, suggesting a potential respiratory risk. The collection had higher contamination levels compared to the storage environment, likely due to improved storage conditions. Even though overall low contamination levels were obtained, these might be underestimated due to the presence of salt (from cod preservation) that could have interfered with the analyses. This study underlines the importance of monitoring microbial communities and implementing proper storage measures to safeguard cultural heritage and staff well-being. [ABSTRACT FROM AUTHOR]

Triazoles are widely used to control pathogenic fungi. They inhibit the ergosterol biosynthetic pathway, but the precise mechanisms leading to fungicidal activities in many fungal pathogens are poorly understood. Here, we elucidate the mode of action of epoxiconazole and metconazole in the wheat pathogen Zymoseptoria tritici and the rice blast fungus Magnaporthe oryzae. We show that both azoles have fungicidal activity and reduce fluidity, but not integrity, of the plasma membrane. This impairs localisation of Cdc15-like F-BAR proteins, resulting in defective actin ring assembly and incomplete septation. However, mutant studies and pharmacological experiments in vitro and in planta show that azole lethality is due to a combination of reactive oxygen species-induced apoptosis and macroautophagy. Simultaneous inhibition of both programmed cell death pathways abolishes azole-induced cell death. Other classes of ergosterol biosynthesis inhibitors also induce apoptosis and macroautophagy, suggesting that activation of these two cell death pathways is a hallmark of ergosterol synthesis-targeting fungicides. This knowledge will inform future crop protection strategies. Antifungal azoles inhibit ergosterol biosynthesis, but how that leads to fungistatic or fungicidal activities in many pathogenic fungi is poorly understood. Here, Schuster, Kilaru & Steinberg show that azole lethality in the plant pathogens Zymoseptoria tritici and Magnaporthe oryzae is due to a combination of reactive oxygen species-induced apoptosis and macroautophagy. [ABSTRACT FROM AUTHOR]

This report describes the one‐pot direct N‐acylation of indazole with carboxylic acids using our previously developed 4‐(N,N‐dimethylamino)pyridine N‐oxide (DMAPO)/di‐tert‐butyl dicarbonate (Boc2O) system. This simple system provides N1‐acyl indazoles in high yield with high N1 selectivities and does not require the use of activated derivatives of carboxylic acids or high temperatures. This new method exhibits a wide substrate scope (>40 examples). In addition, a new synthesis of N1‐functionalized alkyl indazoles utilizing N1‐acyl indazoles as starting materials was achieved. This stepwise protocol is useful for the selective synthesis of structurally diverse N1‐functionalized alkyl indazoles, which are difficult to synthesize by other methods such as the Mitsunobu reaction and classical SN2 alkylation of indazole. [ABSTRACT FROM AUTHOR]

A novel electrochemical method is described for the direct oxidative C--N coupling of tetrahydroquinolines and azoles, enabling the synthesis of dihydroquinoline derivatives under mild reaction conditions. In this approach, 2,2,6,6-tetramethylpiperidinooxy (TEMPO) serves as a redox mediator, and NaI not only acts as an electrolyte but also functions as an iodine mediator. The reaction exhibits good functional group tolerance and high atomic economy, resulting in moderate to excellent yields of the desired dihydroquinoline derivatives. Furthermore, by adjusting the reaction conditions, the corresponding quinoline derivatives can also be selectively obtained. [ABSTRACT FROM AUTHOR]

General, catalytic and enantioselective construction of chiral α,α-dialkyl indoles represents an important yet challenging objective to be developed. Herein we describe a cobalt catalyzed enantioselective anti-Markovnikov alkene hydroalkylation via the remote stereocontrol for the synthesis of α,α-dialkyl indoles and other N-heterocycles. This asymmetric C(sp3)−C(sp3) coupling features high flexibility in introducing a diverse set of alkyl groups at the α-position of chiral N-heterocycles. The utility of this methodology has been demonstrated by late-stage functionalization of drug molecules, asymmetric synthesis of bioactive molecules, natural products and functional materials, and identification of a class of molecules exhibiting anti-apoptosis activities in UVB-irradiated HaCaT cells. Ligands play a vital role in controlling the reaction regioselectivity. Changing the ligand from bi-dentate L6 to tridentate L12 enables CoH-catalyzed Markovnikov hydroalkylation. Mechanistic studies disclose that the anti-Markovnikov hydroalkylation involves a migratory insertion process while the Markovnikov hydroalkylation involves a MHAT process. Catalytic and enantioselective construction of chiral α,α-dialkyl indoles represents an important yet challenging objective to be developed. Herein the authors describe a cobalt catalyzed enantioselective anti-Markovnikov alkene hydroalkylation via the remote stereocontrol for the synthesis of α,α-dialkyl indoles and other N-heterocycles. [ABSTRACT FROM AUTHOR]

Breast cancer, an epithelial malignant tumor that occurs in the terminal ducts of the breast, represents the most prevalent malignancy in women, with over 2 million new diagnoses annually throughout the world. Chemotherapy remains a mainstay in breast cancer therapy, but drug resistance and severe side effects are the major causes for treatment failure. Sulfonamides could act on diverse proteins, enzymes, and receptors and demonstrated promising anti-breast cancer potential. In particular, sulfonamide hybrids have the potential to overcome drug resistance and reduce the side effects since hybrid molecules could act on dual/multiple targets simultaneously. This review focuses on the anti-breast cancer activity, structure-activity relationships, and mechanisms of action of sulfonamide-five-membered heterocycle hybrids, including sulfonamide-azole hybrids, sulfonamide-7-azaindole/indole/oxindole/indoline hybrids, sulfonamide-furan hybrids, and sulfonamide-thiophene hybrids, covering articles published from 2020 to present, to open new avenues for the exploration of novel more effective and multitargeted candidates. [ABSTRACT FROM AUTHOR]

Candida albicans and C. glabrata express exporters of the ATP-binding cassette (ABC) superfamily and address them to their plasma membrane to expel azole antifungals, which cancels out their action and allows the yeast to become multidrug resistant (MDR). In a way to understand this mechanism of defense, we describe the purification and characterization of Cdr1, the membrane ABC exporter mainly responsible for such phenotype in both species. Cdr1 proteins were functionally expressed in the baker yeast, tagged at their C-terminal end with either a His-tag for the glabrata version, cg Cdr1-His, or a green fluorescent protein (GFP) preceded by a proteolytic cleavage site for the albicans version, ca Cdr1-P-GFP. A membrane Cdr1-enriched fraction was then prepared to assay several detergents and stabilizers, probing their level of extraction and the ATPase activity of the proteins as a functional marker. Immobilized metal-affinity and size-exclusion chromatographies (IMAC, SEC) were then carried out to isolate homogenous samples. Overall, our data show that although topologically and phylogenetically close, both proteins display quite distinct behaviors during the extraction and purification steps, and qualify cg Cdr1 as a good candidate to characterize this type of proteins for developing future inhibitors of their azole antifungal efflux activity. • This paper describes the purification of a clinically relevant drug transporter of pathogenic fungi • It includes a detailed methodology on working with membrane proteins, including detergent screening, purification and characterization • The use of fluorescence quenching allows to measure the affinity of the protein for its ligands • NanoDifferential Scanning Fluorimetry showed a differential stabilization of the protein, thus making it an interesting tool to screen for future inhibitors • The purification of an ATPase active protein paves the way for structural studies of these transporters. [ABSTRACT FROM AUTHOR]

The wheat scab caused by Fusarium graminearum (F. graminearum) has seriously affected the yield and quality of wheat in China. In this study, gallic acid (GA), a natural polyphenol, was used to synthesize three azole-modified gallic acid derivatives (AGAs1–3). The antifungal activity of GA and its derivatives against F. graminearum was studied through mycelial growth rate experiments and field efficacy experiments. The results of the mycelial growth rate test showed that the EC50 of AGAs–2 was 0.49 mg/mL, and that of AGAs–3 was 0.42 mg/mL. The biological activity of AGAs–3 on F. graminearum is significantly better than that of GA. The results of field efficacy tests showed that AGAs–2 and AGAs–3 significantly reduced the incidence rate and disease index of wheat scab, and the control effect reached 68.86% and 72.11%, respectively. In addition, preliminary investigation was performed on the possible interaction between AGAs–3 and F. graminearum using density functional theory (DFT). These results indicate that compound AGAs–3, because of its characteristic of imidazolium salts, has potential for use as a green and environmentally friendly plant-derived antifungal agent for plant pathogenic fungi. [ABSTRACT FROM AUTHOR]

We report an innovative synthetic strategy for the generation of polysubstituted indoles from indolines, aryldiazonium salts, and azoles. The methodology encompasses an electrophilic substitution reaction affording C5-indoline intermediates which undergo an iodine-mediated oxidative transformation coupled with C–H functionalization to yield the indole derivatives. [ABSTRACT FROM AUTHOR]

Background: The use of contraceptive devices predisposes women to vulvovaginal candidiasis (VVC) globally. Despite the high incidence of VVC and antifungal resistance to azoles, the genetic diversity and resistance pattern among contraceptive users in Nigeria is poorly investigated. This study therefore sought to characterize and determine the phylogenetic breadth of Candida species as well as their resistance to antifungal agents. Methodology: This study recruited 1,600 women using contraceptive devices who visited selected gynaecology and obstetrics clinics in northcentral Nigeria. Candida species were isolated and characterized using conventional methods and sequencing of the internal transcribed spacer (ITS) region of the ribosomal DNA (rDNA). Bayesian phylogenetic analysis was used to characterize the diversity of Candida species and primer-specific PCR was used to detect the presence of resistant genes. Agar well diffusion technique was used for the determination of antifungal susceptibility profiles. Data analysis was done by Kruskal-Wallis Chi-square test on R Console software version 3.2.2, followed by post-hoc Wilcoxon rank sum test with Bonferroni correction for multiple pairwise comparisons of means where there was a significant difference between the antifungal agents. The level of significance was set at p < 0.05. Results: A total of 710 (44.3%) out of the 1,600 women using contraceptive devices had VVC with five species of Candida identified in them. Although Candida albicans was the predominant (43.2%, n=307) species, other non-albicans Candida species include Candida (Nakaseomyces) glabrata (19.0%, n=135), Candida tropicalis (15.8%, n=112), Candida parapsilosis (8.9%, n=63), and Candida akabanensis (13.1%, n=93) which were phenotypically identified as Candida (Nakaseomyces) glabrata. All the Candida species showed varying degrees of susceptibilities to voriconazole, fluconazole and nystatin. However, resistance of C. albicans to fluconazole was 29.0%, C. tropicalis to nystatin (46.0%) and to voriconazole (14.0%), while C. akabanensis was 100.0% resistant to voriconazole and fluconazole. Kruskal-Wallis Chi-square test showed nystatin as the most effective antifungal agent against the Candida species (χ²=786.03, df=2, p<0.001). Also, resistant gene Erg11 was identified in all the Candida species that were phenotypically resistant to the antifungal agents tested. Conclusion: Women using contraceptive devices in northcentral Nigeria harbor phylogenetically diverse Candida species including C. akabanensis, an uncommon cause of VVC. Of these Candida species, C. albicans, C. tropicalis and C. akabanensis were notable for multidrug drug resistance as well as harboring Erg11 resistance gene. [ABSTRACT FROM AUTHOR]

The emergence of azole-resistant Aspergillus fumigatus (ARAf) across the world is an important public health concern. We sought to determine if propiconazole, a demethylase inhibitor (DMI) fungicide, exerted a selective pressure for ARAf in a tomato production environment following multiple exposures to the fungicide. A tomato field trial was established in 2019 and propiconazole was applied weekly until harvest. Soil, leaf, and fruit (when present) samples were collected at baseline and after each propiconazole application. A. fumigatus isolates (n, 178) were recovered and 173 were tested for susceptibility to itraconazole, posaconazole, voriconazole, and propiconazole in accordance with CLSI M38 guidelines. All the isolates were susceptible to medical triazoles and the propiconazole MIC ranged from 0.25 to 8 mg/L. A linear regression model was fitted that showed no longitudinal increment in the log2-fold azole MIC of the isolates collected after each propiconazole exposure compared to the baseline isolates. AsperGenius real-time multiplex assay ruled out TR34/L98H and TR46/Y121F/T289A cyp51A resistance markers in these isolates. Sequencing of a subset of isolates (n, 46) demonstrated widespread presence of F46Y/M172V/E427K and F46Y/M172V/N248T/D255E/E427K cyp51A mutations previously associated with reduced susceptibility to triazoles. IMPORTANCE The agricultural use of azole fungicides to control plant diseases has been implicated as a major contributor to ARAf infections in humans. Our study did not reveal imposition of selection pressure for ARAf in a vegetable production system. However, more surveillance studies for ARAf in food crop production and other environments are warranted in understanding this public and One Health issue. [ABSTRACT FROM AUTHOR]

Candida parapsilosis is one of the most commen causes of life-threatening candidaemia, particularly in premature neonates, individuals with cancer of the haematopoietic system, and recipients of organ transplants. Historically, drug-susceptible strains have been linked to clonal outbreaks. However, worldwide studies started since 2018 have reported severe outbreaks among adults caused by fluconazole-resistant strains. Outbreaks caused by fluconazole-resistant strains are associated with high mortality rates and can persist despite strict infection control strategies. The emergence of resistance threatens the efficacy of azoles, which is the most widely used class of antifungals and the only available oral treatment option for candidaemia. The fact that most patients infected with fluconazole-resistant strains are azole-naive underscores the high potential adaptability of fluconazole-resistant strains to diverse hosts, environmental niches, and reservoirs. Another concern is the multidrug-resistant and echinocandin-tolerant C parapsilosis isolates, which emerged in 2020. Raising awareness, establishing effective clinical interventions, and understanding the biology and pathogenesis of fluconazole-resistant C parapsilosis are urgently needed to improve treatment strategies and outcomes.

The cultivation of oil palms is of great importance in the global agricultural industry due to its role as a primary source of vegetable oil with a wide range of applications. However, the sustainability of this industry is threatened by the presence of pathogenic fungi, particularly Ganoderma spp., which cause detrimental oil palm disease known as basal stem rot (BSR). This unfavorable condition eventually leads to significant productivity losses in the harvest, with reported yield reductions of 50–80 % in severely affected plantations. Azole-based fungicides offer potential solutions to control BSR, but their efficacy is hampered by limited solubility, penetration, distribution, and bioavailability. Recent advances in nanotechnology have paved the way for the development of nanosized delivery systems. These systems enable effective fungicide delivery to target pathogens and enhance the bioavailability of azole fungicides while minimising environmental and human health risks. In field trials, the application of azole-based nanofungicides resulted in up to 75 % reduction in disease incidence compared to conventional fungicide treatments. These innovations offer opportunities for the development of sustainable agricultural practices. This review highlights the importance of oil palm cultivation concerning the ongoing challenges posed by pathogenic fungi and examines the potential of azole-based fungicides for disease control. It also reviews recent advances in nanotechnology for fungicide delivery, explores the mechanisms behind these nanodelivery systems, and emphasises the opportunities and challenges associated with azole-based nanofungicides. Hence, this review provides valuable insights for future nanofungicide development in effective oil palm disease control.

Wickerhamiella is a genus of budding yeast that is mainly isolated from environmental samples, and 40 species have been detected. The yeast isolated from human clinical samples usually only contain three species: W. infanticola, W. pararugosa and W. sorbophila. In this study, we isolated W. tropicalis from a blood sample of a six-year-old female with a history of B-cell precursor lymphoblastic leukemia in Japan in 2022. Though the strain was morphologically identified as Candida species by routine microbiological examinations, it was subsequently identified as W. tropicalis by sequencing the internal transcribed spacer (ITS) of ribosomal DNA (rDNA). The isolate had amino acid substitutions in ERG11 and FKS1 associated with azole and echinocandin resistance, respectively, in Candida species and showed intermediate-resistant to fluconazole and micafungin. The patient was successfully treated with micafungin. Furthermore, matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) detected three novel peaks that are specific for W. tropicalis, indicating that MALDI-MS analysis is useful for rapid detection of Wickerhamiella species in routine microbiological examinations. [ABSTRACT FROM AUTHOR]

Aspergillus fumigatus is a pathogenic fungus with a global distribution. The emergence of azole-resistant A. fumigatus (ARAf) other than the TR-mutants is a problem in Japan. Additionally, the genetic diversity of A. fumigatus strains in Japan remains relatively unknown. Here we show the diversity in the A. fumigatus strains isolated in Japan as well as the complexity in the global distribution of the pathogenic strains. First, we analyzed the genome sequences of 171 strains from Japan as well as the antifungal susceptibility of these strains. Next, we conducted a population analysis of 876 strains by combining the available genomic data for strains isolated worldwide, which were grouped in six clusters. Finally, a genome-wide association study identified the genomic loci associated with ARAf strains, but not the TR-mutants. These results highlight the complexity of the genomic mechanism underlying the emergence of ARAf strains other than the TR-mutants. Whole-genome analysis of 876 Aspergillus fumigatus strains including 171 strains from Japan highlights the diversity in the A. fumigatus strains isolated in Japan as well as the complexity in the global distribution of the pathogenic strains. [ABSTRACT FROM AUTHOR]

Environment-benign one-pot three-component cycloadditions of diazo compounds, nitrosoarenes and vinyl pyrimidines, or vinyl purines, or vinyl imidazoles, or vinyl triazoles or vinyl indole have been developed. This catalyst- and additive-free strategy could efficiently introduce the isoxazolidine skeleton into nucleoside analogues, oxazole molecules and indole derivatives to provide diverse classes of isoxazolidinyl pyrimidine nucleoside analogues, isoxazolidinyl purine nucleoside analogues, isoxazolidinyl imidazoles, isoxazolidinyl triazoles and isoxazolidinyl indole with moderate to good yields for most substrates. [ABSTRACT FROM AUTHOR]

Reported herein is a photochemical strategy for C(sp3)–H azolation of ethers via a hydrogen-atom transfer and radical-polar crossover process, offering efficient access to valuable N-alkylated azoles under visible-light irradiation. The protocol is metal-free and photocatalyst-free, and exhibits good to excellent yields and broad substrate scope with regard to azoles. EPR experiments provide evidence for the formation of intermediates formed in situ. [ABSTRACT FROM AUTHOR]

Sterically-hindered N-heterocyclic carbenes (NHCs) with functionalized N-wingtips are a pivotal class of ligands in organic synthesis. Herein, we report the first class of sterically-hindered N-heterocyclic carbenes based on the indazole framework. These ligands combine the strong σ-donation of the carbene center due to the carbene placement at the C3-indazole position with the sterically-hindered and flexible N-substitution with the versatile 2,6-bis(diphenylmethyl)aryl moiety that extends beyond the metal centre for the first time in non-classical N-heterocyclic carbenes. The ligands are readily accessible by the rare Cadogan indazole synthesis of sterically-hindered N-aryl-1-(2-nitrophenyl)methanimines. Steric and electronic characterization as well as catalytic studies in the synthesis of oxazolines are described. Considering the unique properties of indazole-derived carbenes, we anticipate that this class of compounds will find broad application in organic synthesis and catalysis. [ABSTRACT FROM AUTHOR]

Background: Fluconazole‐resistant Candida parapsilosis is a matter of concern. Objectives: To describe fluconazole‐resistant C. parapsilosis genotypes circulating across hospitals in Spain and Rome and to study their azole‐resistance profile associated with ERG11p substitutions. Patients/Methods: We selected fluconazole‐resistant C. parapsilosis isolates (n = 528 from 2019 to 2023; MIC ≥8 mg/L according to EUCAST) from patients admitted to 13 hospitals located in five Spanish cities and Rome. Additionally, we tested voriconazole, posaconazole, isavuconazole, amphotericin B, micafungin, anidulafungin and ibrexafungerp susceptibility. Results: Of the 53 genotypes found, 49 harboured the Y132F substitution, five of which were dominating city‐specific genotypes involving almost half the isolates. Another genotype involved isolates harbouring the G458S substitution. Finally, we found two genotypes with the wild‐type ERG11 gene sequence and one with the R398I substitution. All isolates were fully susceptible/wild‐type to amphotericin B, anidulafungin, micafungin and ibrexafungerp. The azole‐resistance patterns found were: voriconazole‐resistant (74.1%) or voriconazole‐intermediate (25.2%), posaconazole‐resistant (10%) and isavuconazole non‐wild‐type (47.5%). Fluconazole‐resistant and voriconazole non‐wild‐type isolates were likely to harbour substitution Y132F if posaconazole was wild type; however, if posaconazole was non‐wild type, substitution G458S was indicated if isavuconazole MIC was >0.125 mg/L or substitution Y132F if isavuconazole MIC was ≤0.125 mg/L. Conclusions: We detected a recent clonal spread of fluconazole‐resistant C. parapsilosis across some cities in Spain, mostly driven by dominating city‐specific genotypes, which involved a large number of isolates harbouring the Y132F ERG11p substitution. Isolates harbouring substitution Y132F can be suspected because they are non‐susceptible to voriconazole and rarely posaconazole‐resistant. [ABSTRACT FROM AUTHOR]

Background: Meyerozyma guilliermondii is a yeast species responsible for invasive fungal infections. It has high minimum inhibitory concentrations (MICs) to echinocandins, the first‐line treatment of candidemia. In this context, azole antifungal agents are frequently used. However, in recent years, a number of azole‐resistant strains have been described. Their mechanisms of resistance are currently poorly studied. Objective: The aim of this study was consequently to understand the mechanisms of azole resistance in several clinical isolates of M. guilliermondii. Methods: Ten isolates of M. guilliermondii and the ATCC 6260 reference strain were studied. MICs of azoles were determined first. Whole genome sequencing of the isolates was then carried out and the mutations identified in ERG11 were expressed in a CTG clade yeast model (C. lusitaniae). RNA expression of ERG11, MDR1 and CDR1 was evaluated by quantitative PCR. A phylogenic analysis was developed and performed on M. guilliermondii isolates. Lastly, in vitro experiments on fitness cost and virulence were carried out. Results: Of the ten isolates tested, three showed pan‐azole resistance. A combination of F126L and L505F mutations in Erg11 was highlighted in these three isolates. Interestingly, a combination of these two mutations was necessary to confer azole resistance. An overexpression of the Cdr1 efflux pump was also evidenced in one strain. Moreover, the three pan‐azole‐resistant isolates were shown to be genetically related and not associated with a fitness cost or a lower virulence, suggesting a possible clonal transmission. Conclusion: In conclusion, this study identified an original combination of ERG11 mutations responsible for pan‐azole‐resistance in M. guilliermondii. Moreover, we proposed a new MLST analysis for M. guilliermondii that identified possible clonal transmission of pan‐azole‐resistant strains. Future studies are needed to investigate the distribution of this clone in hospital environment and should lead to the reconsideration of the treatment for this species. [ABSTRACT FROM AUTHOR]

The incidence of infections caused by Candida species, specifically by drug-resistant isolates, is a major health concern as they can disseminate to and colonize most vital organs, enhancing morbidity and mortality. Several molecular mechanisms have been reported to be involved in drug resistance. These are mostly drug- and isolate-specific. Here, we characterized three different genetically modified strains of C. albicans that were multi-drug-resistant (MDR) and deciphered a uniform mechanism responsible for resistance. DNA polymerase epsilon (Polε) is a leading strand-specific polymerase consisting of four subunits, namely, Pol2, Dpb2, Dpb3, and Dpb4. The deletion of one or both of the Dpb3 and Dpb4 subunits in C. albicans rendered multi-drug resistance. A detailed characterization of these strains revealed that acquired mutagenesis, drug efflux pumps, and other known mechanisms did not play a significant role because the complemented strain showed drug sensitivity. More importantly, the function of heat shock protein 90 (Hsp90) in these knockout strains is critical for reducing susceptibility to several antifungal drugs. Cell wall deformity and composition in these strains can add to such a phenotype. The inhibition of Hsp90 function by geldanamycin and tricostatin A sensitized the MDR strains to antifungals. Considering our earlier research and this report, we suggest that replication stress induces Hsp90 expression and activity in order to orchestrate a cellular stress response circuit and thus develop fungal drug resistance. Thus, Hsp90 is an important drug target for use in combinatorial therapy. [ABSTRACT FROM AUTHOR]

This article provides information on the management and treatment of otitis externa in dogs. It emphasizes the importance of understanding the underlying factors and using a two-phase approach: reactive therapy to treat acute/chronic lesions and infection, and proactive therapy for long-term maintenance and prevention of flares. The article also highlights the use of appropriate ear cleaners and techniques, the challenges posed by biofilms, and the need for broad-spectrum anti-inflammatory treatment to reverse pathological changes. Additionally, it addresses the importance of pain management and training dogs to accept topical treatment. Overall, effective management of otitis externa can greatly improve the quality of life for dogs and their owners. [Extracted from the article]

Nitrogen‐rich energetic materials based on five‐membered azoles, such as tetrazoles, triazoles, oxadiazoles, pyrazoles, and imidazoles, have garnered significant attention in recent years due to their environmental compatibility while maintaining high performance. These materials, including explosives, propellants, and pyrotechnics, are designed to release energy rapidly and efficiently while minimizing the release of toxic or hazardous byproducts and have attracted potential applications in the defense and space industries. The presence of extensive NC, NN, and NN high energy bonds in azoles provides high enthalpies of formation and facilitates intermolecular interactions through π‐stacking which may help with reducing sensitivity to external stimuli. Now, we report on the synthesis and energetic properties of N‐(5‐(1H‐tetrazol‐5‐yl)‐1,3,4‐oxadiazol‐2‐yl)nitramide (5) and its energetic salts. These new high nitrogen–oxygen‐containing materials have attractive feature applications of insensitivity and increased performance. [ABSTRACT FROM AUTHOR]

Electrolytes are considered the lifeblood of lithium batteries, facilitating ion transfer between the cathode and anode. However, the flammability, volatility and corrosiveness of organic electrolytes impede the sustainable development of lithium batteries. Deep eutectic electrolytes (DEEs) have emerged as a promising alternative, exhibiting high stability, non-flammability and wide electrochemical window. Herein, a series of DEEs with varying molar ratios of azoles and LiTFSI were facilely prepared through the interaction of Li⋯N. These DEEs demonstrate unique advantages, including non-flammability, high conductivity and a favourable Li+ transference number. In particular, the DEEs ImL-4:1 and PyL-4:1 (Imidazole:LiTFSI = 4:1 and Pyrazole:LiTFSI = 4:1, respectively) achieve high ionic conductivities of 4.5 × 10−3 and 5.8 × 10−3 S cm−1 at 80 °C, respectively. Notably, the electrochemical window of PyL-4:1 is stable, making it a suitable electrolyte for the lithium metal-free Li 4 Ti 5 O 12 /LiFePO 4 full battery. This system exhibits an initial specific capacity of 147 mAh g−1 and maintains stable cycling performance over 200 cycles. This study offers valuable insights into the design of electrolytes, addressing the challenges posed by traditional organic electrolytes and paving the way for sustainable lithium battery development. [ABSTRACT FROM AUTHOR]

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(1) Background: Despite being considered a non-pathogenic yeast, recently, a growing occurrence of Saccharomyces cerevisiae infections has been noted. There is little knowledge about the drug susceptibility of this species. Therefore, the objective of this research was to expand it and determine the drug susceptibility profile of a local collection of clinical isolates of this species. (2) Methods: This study contained 55 clinical isolates identified as Saccharomyces cerevisiae using the MALDI-TOF method. The susceptibility of Saccharomyces cerevisiae was tested to 10 antifungals (amphotericin B, flucytosine, fluconazole, voriconazole, posaconazole, micafungin, anidulafungin, caspofungin, and itraconazole) using MICRONAUT-AT tests and manogepix, a new drug, using the microdilution method according to EUCAST. (3) Results: Overall, most strains were classified as sensitive to amphotericin B and flucytosine (MIC ranges of ≤0.03–1 and ≤0.06–0.125, respectively) and also to echinocandins. However, five isolates expressed high MIC values for all of the tested azoles, indicating cross-resistance. The MIC range for manogepix was 0.001–0.125 mg/L, with an MIC50 of 0.03 mg/L and an MIC90 of 0.06 mg/L. (4) Conclusions: The occurrence of resistance to azoles may be a concerning problem and therefore should be investigated further. However, the new antifungal manogepix appears to be an interesting new therapeutic option for treating such infections. [ABSTRACT FROM AUTHOR]