Antifungal Drug Resistance: An Emergent Health Threat

Vitiello, Antonio; Ferrara, Francesco; Boccellino, Mariarosaria; Ponzo, Annarita; Cimmino, Carla; Comberiati, Emilio; Zovi, Andrea; Clemente, Salvatore; Sabbatucci, Michela

doi:10.3390/biomedicines11041063

Cited by 76 publications

(31 citation statements)

References 59 publications

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“…Then, the mixture was allowed to be heated to room temperature and was stirred for 16 h. The reaction mixture was washed three times with H 2 Oand brine, the organic layer was collected, dried with Na 2 SO 4, and removed in vacuo to afford the crude product, which was purified by flash column chromatography to give N-Boc-1-aminocyclobutanecarboxylic-carbohydrazide 4. General Synthesis Procedure for Substituted 1-Aminocyclobutanecarboxylic-carbohydrazide (5). To a solution of N-Boc-1aminocyclobutanecarboxylic-carbohydrazide 5 (2.0 mmol) in DCM (10.0 mL) was added TFA (30.0 mmol) at 0 °C.…”

Section: ■ Materials and Methodsmentioning

confidence: 99%

“…2,3 In addition to endangering food security, human and animal's health, the development of phytopathogenic fungi in host plants have permanently disturbed the normal metabolic equilibrium inside living creatures. 4,5 The control of phytopathogenic fungi mainly depends on the repeated use of chemical fungicides, which causes rapid development of resistance. 6 The resistance of triazoles and QoI inhibitors (strobilurins) seriously affects agricultural security.…”

Section: ■ Introductionmentioning

confidence: 99%

“…Fungi as a class of eukaryotic microorganisms extensively exist in natural environments . Phytopathogenic fungi have long been regarded as severe threat to crops, and their infections on crops are the most devastating diseases, which account for 16% of crop losses worldwide. , In addition to endangering food security, human and animal’s health, the development of phytopathogenic fungi in host plants have permanently disturbed the normal metabolic equilibrium inside living creatures. , The control of phytopathogenic fungi mainly depends on the repeated use of chemical fungicides, which causes rapid development of resistance . The resistance of triazoles and QoI inhibitors (strobilurins) seriously affects agricultural security. − To address these issues, the environmentally friendly and low toxic agricultural fungicides have become a crucial subject of research.…”

Section: Introductionmentioning

confidence: 99%

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Discovery of Novel Aminocyclobutanecarboxylic Acid Derivatives as Succinate Dehydrogenase Inhibitors

Zhang

et al. 2023

J. Agric. Food Chem.

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The conformational restriction switch concept has been adopted as a major tool for structural optimization of pharmaceuticals in order to expand the chemical structure scope and improve therapeutic activity against specific proteins. Several of the 1-aminocyclobutanecarboxylic acid derivatives produced in this way exhibited satisfactory antifungal activity in vitro compared with positive control boscalid. In vitro antifungal tests revealed that compound A21 had comparable, even higher antifungal activity against Rhizoctonia solani (R.s., EC 50 = 0.03 mg/L) and Botrytis cinerea (B.c., EC 50 = 0.04 mg/L) than fluxapyroxad (R.s., EC 50 = 0.02 mg/L; B.c., EC 50 = 0.20 mg/L) and boscalid (R.s., EC 50 = 0.29 mg/L; B.c., EC 50 = 0.42 mg/L). Furthermore, compound A20 was successfully screened and exhibited good inhibitory activity against porcine SDH, its IC 50 value was 3.73 μM, which has considerable potency compared with fluxapyroxad (IC 50 = 3.76 μM). The mode of action was determined using SEM and membrane potential research. The effects of the substituent steric hindrance, electrostatic property, hydrophobicity, and hydrogen-bond fields on structure−activity relationships were elaborated by the reliable models of comparative molecular field analysis and comparative molecular similarity index analysis. Furthermore, density functional theory simulations, molecule electrostatic potential, and molecular docking were also used to study the probable binding mode of target compounds with flexible fragments. The results showed that the scaffold of 1-aminocyclobutanecarboxylic acid derivatives could be used as lead for discovering new succinate dehydrogenase inhibitors.

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Section: ■ Materials and Methodsmentioning

confidence: 99%

Section: ■ Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Discovery of Novel Aminocyclobutanecarboxylic Acid Derivatives as Succinate Dehydrogenase Inhibitors

Zhang

et al. 2023

J. Agric. Food Chem.

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“…infection. 7,8 The ability of C. albicans to invade deep tissues and organs for systemic infection is primarily attributed to the pathogen's morphological transition from single budding yeast cells to hyphal filaments in response to the environmental stimuli of a host's skin. [9][10][11] This is the mechanism by which C. albicans adheres to host tissues and forms invasive biofilms, which is an important step in pathogenesis.…”

Section: Introductionmentioning

confidence: 99%

Sinefungin, a natural nucleoside analog of S-adenosyl methionine, impairs the pathogenicity ofCandida albicans

Nayak,

Chavarria,

Sanders

et al. 2023

Preprint

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Candida albicans, an opportunistic fungal human pathogen, is a major threat to the healthcare system due to both infections in immunocompromised individuals and the emergence of antifungal resistance. Fungal infection caused by C. albicans, candidiasis, is a life-threatening condition in immunocompromised patients and the current treatments are mostly restricted to polyenes, azoles, and echinocandins. Use of these antifungals is limited by toxicity, drug-drug interactions, and the emergence of resistance, underscoring the importance of identifying novel therapeutic targets and the need for new treatment approaches. C. albicans can undergo a morphological transition from yeast to hyphae and this transition is central to C. albicans virulence. Here, we determine the impact of sinefungin, a natural nucleoside analog of S-adenosyl methionine, on the virulence of C. albicans strain SC5314 by evaluating treatment effects on the morphological transition, human epithelial cell adhesion, and biofilm formation. Our data indicate that sinefungin impairs pathogenic traits of C. albicans including hyphal lengthening, biofilm formation and the adhesion to the human epithelial cell lines, without adversely affecting human cells, therefore highlighting sinefungin as a potential avenue for therapeutic intervention. We determine that the formation of N6-methyladenosine (m6A) is particularly disturbed by sinefungin. More broadly, this study underscores the importance of considering the post-transcriptional control mechanisms of pathogenicity when designing therapeutic solutions to fungal infection.

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“…These antibiotics have been synthetically unexamined for close to 50 years. ,− Our laboratory has a deep interest in the development of new reactions which would enable the syntheses of complex antibiotics. Specifically, we envisioned that our laboratory’s sulfamate-tethered aza-Wacker cyclization could serve as a key step for the assembly of the kasugamine portion of these antibiotics. − Our interest in designing practical synthetic routes to antibiotics with new mechanisms of action − relative to approved agents is motivated by the global rise in resistance to antibacterial and antifungal agents currently in use. − It is our hope that de novo syntheses will allow for the rapid preparation of analogues − and will serve as a start of a drug-discovery effort to replenish worrisome antibacterial and antifungal pipelines. In this note, we describe our preparation of a kasugamine synthon, a common building block for both kasugamycin and minosaminomycin.…”

mentioning

confidence: 99%