JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
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2025
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IF 6.2
Zhiyun Li,Saili Xu,Menglan Li,Wenhao Xu,Dang Cheng,Zhiran Ju,Fen-Er Chen
Isavuconazole, a clinically important triazole antifungal drug, relies on α-hydroxymethyl ketone as a key synthetic precursor. Here, we present a novel chemo-enzymatic approach for the synthesis of isavuconazole. Using 2,5-difluorobenzaldehyde as the starting material, engineered benzaldehyde lyase (BAL) catalyzes the crucial benzoin reaction to form the key intermediate α-hydroxymethyl ketone. Notably, this biocatalytic process operates without extra cofactors (thiamine pyrophosphate, ThDP) and Mg2+, achieving a time-space yield (TSY) of 17.2 g·L–1·day–1 under optimized conditions. After further chemical reactions on the intermediate, isavuconazole is obtained through an eco-friendly process that outshines traditional chemical synthesis. This optimized protocol is efficient and scalable, yielding isavuconazole at 28.9%, double that of the current industrial chemical process (14.2%), highlighting the remarkable advantages of enzyme-catalyzed synthesis.
研究领域:
药物化学
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生物催化
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合成生物学
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抗真菌药物研发
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绿色制药
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PubMed
高影响因子
Frontiers in Microbiology
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2025
·
IF 4.5
Mengmin Liang,Qingwen Hu,Junhao Yu,Heng Zhang,Sijie Liu,Jiangrong Huang,Yi Sun
Background: Invasive fungal infections (IFIs) constitute a significant health challenge, particularly among immunocompromised individuals, characterized by a high prevalence and associated mortality rates. The synergistic administration of Baicalein (BE) with azole antifungal agents could potentially herald a novel therapeutic paradigm.Materials and methods: 54 Aspergillus strains and 23 strains of dematiaceous fungi were selected. The standard M38-A2 microbroth dilution method was used to test the minimum inhibitory concentration (MIC) and the fractional inhibitory concentration index (FICI) of fungi when BE combined with itraconazole (ITC), voriconazole (VRC), posaconazole (POS) and Isavuconazole (ISV).Results: BE shows synergistic effects with POS and ITC, with 89.61% and 25.97% of fungal strains. The BE/POS regimen exerted synergistic effects in 87.04% of Aspergillus and an impressive 95.65% of dematiaceous fungi. In comparison, the BE/ITC combination showed significantly lower synergy, affecting 33.33% of Aspergillus and a mere 8.70% of dematiaceous strains. Antagonistic interactions were sporadically observed with BE in combination with ITC, VRC, POS and ISV. Within the azole class, the BE/POS pairing stood out for its frequent synergistic activity, in contrast to the absence of such effects when BE was paired with VRC or ISV. Highlighting the potential of BE/POS as a notably effective antifungal strategy.Conclusion: In vitro, BE/POS combination emerged as the most effective antifungal strategy, exhibiting synergistic effects in the majority of Aspergillus and dematiaceous fungi strains, whereas BE/ITC showed significantly less synergy, and BE with VRC or ISV displayed no synergistic activity.
研究领域:
医学
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微生物学
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药理学
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DOI
PubMed
高影响因子
Microbiology Spectrum
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2025
·Vol. 13
·期 8
·
IF 3.8
Tian Chen,Shaolan Liu,Fei Yang,Zhangxuan He,Menghua Tang,Lu Ge,Hongyi Zhang,Sijie Liu,Xiaolei Zhu,Mengqi Peng,Heng Zhang,Wenxu Cheng,Yi Sun
Invasive fungal infections and emerging antifungal resistance mediated by pathogenic fungi, notably Candida spp., Aspergillus spp., Cryptococcus neoformans, and Exophiala dermatitidis, pose a critical challenge to global public health systems. This study evaluated the synergistic antifungal activity of oleanolic acid (OA) combined with five azole agents (itraconazole [ITR], voriconazole [VOR], posaconazole [POS], isavuconazole [ISA], and fluconazole) against Candida spp., Aspergillus spp., E. dermatitidis, and C. neoformans. Using CLSI-compliant broth microdilution assays (M27-A3/M38-A2), we determined the minimum inhibitory concentrations (MICs) of oleanolic acid against four fungal pathogens and evaluated in vitro synergistic interactions with five azoles to assess their therapeutic potential. OA exhibited no intrinsic fungicidal activity when administered alone. However, synergistic inhibition was observed in specific azole combinations across tested pathogens: Candida spp. (n = 18) demonstrated 33% (6/18) and 56% (10/18) synergy rates with ITR and POS, respectively. Aspergillus spp. (n = 30) showed enhanced synergism at 80% (24/30) for ITR and 97% (29/30) for POS. All OA-azole combinations were synergistic against C. neoformans (n = 8), with rates of 75% (6/8) for ITR, 75% (6/8) for VOR, 87.5% (7/8) for ISA, and 100% (8/8) for POS. In contrast, E. dermatitidis (n = 21) responded only to OA/POS (52%, 11/21). Overall synergistic frequencies were POS (75%, 58/77) > ITR (47%, 36/77) > ISA (9%, 7/77) > VOR (8%, 6/77). The OA-azole combinations demonstrated significant reductions in azole MIC values and exhibited synergistic antifungal activity, particularly against Aspergillus spp. and C. neoformans. While the mechanistic basis of OA’s chemosensitization remains uncharacterized, its multi-target pharmacological profile underscores potential utility in combating antifungal resistance.
研究领域:
医学真菌学
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药理学
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微生物学
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抗菌素耐药性
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药物协同
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DOI
PubMed
高影响因子
MYCOPATHOLOGIA
·
2025
·Vol. 190
·期 5
·1-13
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IF 2.9
Han Xiang,Zhang Heng,Mao Yuqi,Ling Wenhao,Ge Lu,Tang Menghua,Sun Yi,Wu Zhiqin
Introduction Fungal keratitis (FK), a severe ocular infection caused primarily by Fusarium spp. and Aspergillus spp., remains a major cause of blindness worldwide. Current treatment relies on antifungal agents, though emerging azole resistance in Aspergillus fumigatus complicates therapeutic outcomes. Materials and methods We isolated a clinical FK strain and assessed its antifungal susceptibility using broth microdilution and E-test methods, followed by sequencing of the cyp51A gene’s promoter region and coding sequence (CDS) to identify resistance-associated mutations. Results The isolate, confirmed as A. fumigatus (Aftr46-001) via ITS and β-tubulin sequencing, exhibited elevated minimum inhibitory concentrations (MICs) 16 µg/mL for itraconazole (ITC), 32 µg/mL for isavuconazole (ISA), 32 µg/mL for voriconazole (VRC), and 1 µg/mL for posaconazole (POS) by broth microdilution. E-test results revealed an ITR MIC of 12 µg/mL, ISA MIC 32 µg/mL, VRC MIC 32 µg/mL, and POS MIC of 2 µg/mL. The isolate exhibited MICs values at or above the CLSI and EUCAST epidemiological cutoff values (ECVs): 1 µg/mL for ITC, ISA, and VRC according to CLSI (with insufficient data to establish a POS ECV), and 1 µg/mL for ITC and VRC, 2 µg/mL for ISA, and 0.25 µg/mL POS per EUCAST criteria. Genotypic analysis identified a 46-nucleotide tandem repeat in the cyp51A promoter and two nonsynonymous mutations (Y46F, F70L). Discussion This represents the first report of a cyp51A TR46/Y46F/F70L-harboring A. fumigatus strain isolated from FK, with potential agricultural environmental origins, suggesting that this mutation may have become a potential driver of azole-resistant FK in areas with high agricultural exposure, urgently needing to be included in local treatment guidelines and active surveillance systems. The isolate’s resistance to all tested azoles underscores the clinical challenge posed by this genotype. Following this combined intervention, the patient's left eye vision improved from counting fingers at 1 m upon admission to a final visual acuity of 0.3, indicating that combined surgery and local high-dose drug delivery can serve as an effective strategy for drug-resistant FK. These findings highlight the importance of monitoring azole-resistant A. fumigatus strains to guide clinical treatment. The global increase in azole drug resistance further highlights the urgency and importance of rapid and accurate pathogen identification and drug resistance testing in the current environment.
研究领域:
医学微生物学
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真菌学
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抗微生物耐药性
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眼科学
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分子生物学
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临床病理学
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DOI
PubMed
高影响因子
Pharmaceuticals
·
2023
·Vol. 16
·期 11
·1537
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IF 4.6
Wenjing Li,Yang Li,Junlong Cai,Yue Wang,Yanan Liu,Hankun Hu,Liang Liu
Systemic antifungal agents are essential for high-risk patients undergoing immunosuppressive therapy or cancer chemotherapy because of the rapid increase in opportunistic fungal infections. Therapeutic drug monitoring is crucial to ensuring the efficacy and safety of antifungal agents owing to their pharmacokinetic variability. In the present study, we developed and validated a quantitative method for the simultaneous detection of seven commonly used antifungal drugs (amphotericin B, isavuconazole, voriconazole, fluconazole, posaconazole, caspofungin, and micafungin) using liquid chromatography-tandem mass spectrometry. Methanol (containing 0.1% formic acid) was used for protein precipitation and only 50 μL of serum was required for the analysis. Chromatographic separation was conducted using a Waters Acquity UPLC C8 column, and one stable isotope-labeled agent and two analogs were used as internal standards. The calibration curves ranged from 0.1 to 50 μg/mL for all agents, and the correlation coefficient (R2) for all calibration curves was above 0.9835. The intra-day precision (1.2–11.2%), inter-day precision (2.4–13.2%), and mean bias values (−10.9 to 13.6%) were within an acceptable range of ±15%. Successful implementation of the developed method in clinical practice would facilitate the effective monitoring of these antifungal agents.Keywords:antifungal agents;therapeutic drug monitoring;LC–MS/MS;simultaneous quantitation;human serum
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PubMed
高影响因子
Thoracic Cancer
·
2023
·Vol. 14
·期 33
·3331-3341
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IF 2.9
Mengming Xia,Xueyi Song,Zebei Lu,Yu Wang,Quan Zhou,Peiwu Geng,Shuanghu Wang,Yunfang Zhou,Qingjun Wu,Aixia Han
Background Lenvatinib is a multitargeted tyrosine kinase inhibitor used in the treatment of a variety of solid tumors. This study aims to investigate the potential pharmacokinetic interactions between lenvatinib and various azoles (ketoconazole, voriconazole, isavuconazole and posaconazole) when orally administered to rats. Methods A total of 30 Sprague–Dawley rats were randomly allocated into five groups and administered 20 mg/kg of ketoconazole, voriconazole, isavuconazole and 30 mg/kg of posaconazole and 0.5% CMC-Na, through gavage for a duration of 7 days prior to the commencement of the experiment. On the final day, the rats were given 10 mg/kg of lenvatinib. The blood concentration of lenvatinib was determined using UPLC-MS–MS. In vitro lenvatinib were incubated with azoles and rat liver microsomes (RLMs) or human liver microsomes (HLMs). Molecular docking was lastly used to examine the binding strength of the enzymes and ligands with Autodock Vina. Results AUC and C max of lenvatinib significantly increased with each of the azoles ( p < 0.05), whereas CLz/F decreased 0.83-flod, 0.41-fold ( p < 0.05) and 0.72-fold ( p < 0.01) in voriconazole, isavuconazole and ketoconazole in rats. The IC50 of lenvatinib with the azoles were 0.237, 1.300, 0.355 and 2.403 μM in RLMs and 0.160, 1.933, 3.622 and 1.831 μM in HLMs. Molecular docking analysis suggested that azoles exhibited a strong binding ability towards the target enzymes. Conclusion It is imperative to acknowledge the potential drug–drug interactions mediated by CYP3A4 between azoles and lenvatinib, as these interactions hold significant implications for their clinical utilization.
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高影响因子
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