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Emerging Microbes & Infections Dec 2024has emerged as a problematic fungal pathogen associated with high morbidity and mortality. Amphotericin B (AmB) is the most effective antifungal used to treat invasive...
has emerged as a problematic fungal pathogen associated with high morbidity and mortality. Amphotericin B (AmB) is the most effective antifungal used to treat invasive fungal candidiasis, with resistance rarely observed among clinical isolates. However, possesses extraordinary resistant profiles against all available antifungal drugs, including AmB. In our pursuit of potential solutions, we screened a panel of 727 FDA-approved drugs. We identified the proton pump inhibitor lansoprazole (LNP) as a potent enhancer of AmB's activity against LNP also potentiates the antifungal activity of AmB against other medically important species of and Our investigations into the mechanism of action unveiled that LNP metabolite(s) interact with a crucial target in the mitochondrial respiratory chain (complex III, known as cytochrome ). This interaction increases oxidative stress within fungal cells. Our results demonstrated the critical role of an active respiratory function in the antifungal activity of LNP. Most importantly, LNP restored the efficacy of AmB in an immunocompromised mouse model, resulting in a 1.7-log (∼98%) CFU reduction in the burden of in the kidneys. Our findings strongly advocate for a comprehensive evaluation of LNP as a cytochrome inhibitor for combating drug-resistant infections.
Topics: Animals; Mice; Amphotericin B; Antifungal Agents; Candida auris; Lansoprazole; Respiration; Cytochromes; Candidiasis
PubMed: 38431850
DOI: 10.1080/22221751.2024.2322649 -
Microbiology Spectrum Jan 2024Multidrug resistance is a rising problem among non- species, such as . This therapeutic problem has been very important during the COVID-19 pandemic. The World Health...
Multidrug resistance is a rising problem among non- species, such as . This therapeutic problem has been very important during the COVID-19 pandemic. The World Health Organization has included in its global priority list of health-threatening fungi, to study this emerging multidrug-resistant species and to develop effective alternative therapies. In the present study, the synergistic effect of the combination of amphotericin B and echinocandins has been demonstrated against blood isolates of . Different susceptibility responses were also observed between aggregative and non-aggregative phenotypes. The antifungal activity of these drug combinations against was also demonstrated in the host model of candidiasis, confirming the suitability and usefulness of this model in the search for solutions to antimicrobial resistance.
Topics: Animals; Humans; Echinocandins; Amphotericin B; Candida auris; Caenorhabditis elegans; Candida; Pandemics; Microbial Sensitivity Tests; Antifungal Agents
PubMed: 38018978
DOI: 10.1128/spectrum.02086-23 -
Emerging Microbes & Infections Dec 2022Drug resistance derived from extracellular vesicles (EVs) is an increasingly important research area but has seldom been described regarding fungal pathogens. Here, we...
Drug resistance derived from extracellular vesicles (EVs) is an increasingly important research area but has seldom been described regarding fungal pathogens. Here, we characterized EVs derived from a triazole-resistant but amphotericin B-susceptible strain of . Nano- to microgram concentrations of EVs prepared from both broth and solid agar cultures could robustly increase the yeast's survival against both pure and clinical amphotericin B formulations in a dose-dependent manner, resulting in up to 16-fold changes of minimum inhibitory concentration. Meanwhile, this effect was not observed upon addition of these EVs to , nor upon addition of EVs to . No change in susceptibilities was observed upon EV treatment for fluconazole, voriconazole, micafungin, and flucytosine. Mass spectrometry indicated the presence of immunogenic-/drug resistance-implicated proteins in EVs, including alcohol dehydrogenase 1 as well as Mp65-like and Xog1-like proteins in high quantities. Based on these observations, we propose a potential species-specific role for EVs in amphotericin B resistance in . These observations may provide critical insights into treatment of multidrug-resistant .
Topics: Amphotericin B; Antifungal Agents; Candida; Candida albicans; Candida auris; Candidiasis; Extracellular Vesicles; Humans; Microbial Sensitivity Tests
PubMed: 35786393
DOI: 10.1080/22221751.2022.2098058 -
Clinical Infectious Diseases : An... May 2019
Topics: Amphotericin B; Antifungal Agents; Humans; Invasive Fungal Infections
PubMed: 31222252
DOI: 10.1093/cid/ciz091 -
Mycopathologia Apr 2023Until recently, little was known about the susceptibility pattern of Cyberlindnera fabianii (Cy. fabianii) planktonic cells and biofilms regarding the most frequently...
Until recently, little was known about the susceptibility pattern of Cyberlindnera fabianii (Cy. fabianii) planktonic cells and biofilms regarding the most frequently administered systemic antifungals, despite the high mortality rate and its potential role in catheter-related infections. In the current study, the activity of fluconazole, amphotericin B and echinocandins (anidulafungin, caspofungin and micafungin) was determined against planktonic and sessile cells of Cy. fabianii clinical isolates (n = 8). Planktonic minimum inhibitory concentrations (MICs) ranged from 1 to 2, from 0.25 to 1, from 0.015 to 0.06, from 0.03 to 0.12 and from 0.25 to 0.5 mg/l for fluconazole, amphotericin B, anidulafungin, caspofungin and micafungin, respectively. One-day-old biofilms were highly resistant to fluconazole (MIC ranged from 512 to > 512) compared to planktonic counterparts, but not to amphotericin B (MIC ranged from 0.25 to 2 mg/l) and echinocandins (MIC ranged from 0.06 to 2 mg/l). Based on the calculated planktonic killing rates, the highest activity was observed in the case of anidulafungin (k values ranged from 0.37 to 2.09), while micafungin, caspofungin, amphotericin B and fluconazole exerted 0.46-1.47, 0.14-0.86, -0.03 to 2.08 and -0.15 to 0.09 killing rate value ranges, respectively. The obtained in vitro planktonic and sessile susceptibility patterns suggest that echinocandins and amphotericin B may be the most reliable treatment option for the treatment of Cy. fabianii infections.
Topics: Echinocandins; Amphotericin B; Fluconazole; Anidulafungin; Caspofungin; Micafungin; Biofilms
PubMed: 36399230
DOI: 10.1007/s11046-022-00688-9 -
The Journal of Antimicrobial... Sep 2023Biofilms are the leading cause of nosocomial infections and are hard to eradicate due to their inherent antimicrobial resistance. Candida albicans is the leading cause...
BACKGROUND
Biofilms are the leading cause of nosocomial infections and are hard to eradicate due to their inherent antimicrobial resistance. Candida albicans is the leading cause of nosocomial fungal infections and is frequently co-isolated with the bacterium Pseudomonas aeruginosa from biofilms in the cystic fibrosis lung and severe burn wounds. The presence of C. albicans in multispecies biofilms is associated with enhanced antibacterial resistance, which is largely mediated through fungal extracellular carbohydrates sequestering the antibiotics. However, significantly less is known regarding the impact of polymicrobial biofilms on antifungal resistance.
RESULTS
Here we show that, in dual-species biofilms, P. aeruginosa enhances the susceptibility of C. albicans to amphotericin B, an effect that was biofilm specific. Transcriptional analysis combined with gene ontology enrichment analysis identified several C. albicans processes associated with oxidative stress to be differentially regulated in dual-species biofilms, suggesting that P. aeruginosa exerts oxidative stress on C. albicans, likely through the secretion of phenazines. However, the mitochondrial superoxide dismutase SOD2 was significantly down-regulated in the presence of P. aeruginosa. Monospecies biofilms of the sod2Δ mutant were more susceptible to amphotericin B, and the susceptibility of these biofilms was further enhanced by exogenous phenazines.
CONCLUSIONS
We propose that in dual-species biofilms, P. aeruginosa simultaneously induces mitochondrial oxidative stress, while down-regulating key detoxification enzymes, which prevents C. albicans mounting an appropriate oxidative stress response to amphotericin B, leading to fungal cell death. This work highlights the importance of understanding the impact of polymicrobial interactions on antimicrobial susceptibility.
Topics: Candida albicans; Amphotericin B; Pseudomonas aeruginosa; Biofilms; Anti-Bacterial Agents; Phenazines; Antifungal Agents
PubMed: 37522316
DOI: 10.1093/jac/dkad228 -
International Journal of Nanomedicine 2014Amphotericin B (AMB) is a polyene antibiotic with broad spectrum antifungal activity, but its clinical toxicities and poor solubility limit the wide application of AMB...
BACKGROUND
Amphotericin B (AMB) is a polyene antibiotic with broad spectrum antifungal activity, but its clinical toxicities and poor solubility limit the wide application of AMB in clinical practice. Recently, new drug-loaded nanoparticles (NPs) - diblock copolymer D-α-tocopheryl polyethylene glycol 1000 succinate-b-poly(ε-caprolactone-ran-glycolide) (PLGA-TPGS) - have received special attention for their reduced toxicity, and increased effectiveness of drug has also been reported. This study aimed to develop AMB-loaded PLGA-TPGS nanoparticles (AMB-NPs) and evaluate their antifungal effects in vitro and in vivo.
METHODS
AMB-NPs were prepared with a modified nanoprecipitation method and then characterized in terms of physical characteristics, in vitro drug release, stability, drug-encapsulation efficiency, and toxicity. Finally, the antifungal activity of AMB-NPs was investigated in vitro and in vivo.
RESULTS
AMB-NPs were stable and spherical, with an average size of around 110 nm; the entrapment efficacy was closed to 85%, and their release exhibited a typically biphasic pattern. The actual minimum inhibitory concentration of AMB-NPs against Candida albicans was significantly lower than that of free AMB, and AMB-NPs were less toxic on blood cells. In vivo experiments indicated that AMB-NPs achieved significantly better and prolonged antifungal effects when compared with free AMB.
CONCLUSION
The AMB-PLGA-TPGS NP system significantly improves the AMB bioavailability by improving its antifungal activities and reducing its toxicity, and thus, these NPs may become a good drug carrier for antifungal treatment.
Topics: Amphotericin B; Animals; Antifungal Agents; Candida albicans; Candidiasis; Colony Count, Microbial; Drug Carriers; Ethylene Glycols; Kidney; Liver; Mice; Nanoparticles; Polyesters; Polyethylene Glycols; Vitamin E
PubMed: 25473279
DOI: 10.2147/IJN.S71623 -
The Journal of Physical Chemistry... May 2024Amphotericin B is a popular antifungal antibiotic, but the exact way it works is still a matter of debate. Here, we used monolayers composed of phosphatidylcholine with...
Amphotericin B is a popular antifungal antibiotic, but the exact way it works is still a matter of debate. Here, we used monolayers composed of phosphatidylcholine with ergosterol as a model of fungal lipid membranes to study drug incorporation from the aqueous phase and analyze the molecular reorganization of membranes underlying the biological activity of the antibiotic. The results show that the internalization of antibiotic molecules into membranes occurs only in the presence of ergosterol in the lipid phase. Comparison of images of solid-supported monolayers obtained by atomic force microscopy and lifetime imaging fluorescence microscopy shows the formation of intramembrane clusters of various sizes in the lipid phase, consisting mainly of antibiotic dimers and relatively large membrane pores (∼15 nm in diameter). The results reveal multiple modes of action of amphotericin B, acting simultaneously, each of which adversely affects the structural properties of the lipid membranes and their physiological functionality.
Topics: Amphotericin B; Phosphatidylcholines; Ergosterol; Antifungal Agents; Microscopy, Atomic Force; Anti-Bacterial Agents; Cell Membrane; Microscopy, Fluorescence
PubMed: 38668706
DOI: 10.1021/acs.jpclett.4c00496 -
Journal of Global Antimicrobial... Dec 2020We reported the pharmacokinetic/pharmacodynamic (PK/PD) targets of a biosimilar generic product of amphotericin B colloidal dispersion (G-ABCD) againstCandida albicans...
OBJECTIVES
We reported the pharmacokinetic/pharmacodynamic (PK/PD) targets of a biosimilar generic product of amphotericin B colloidal dispersion (G-ABCD) againstCandida albicans (MIC 1-2 μg/mL) in a rat model of invasive candidiasis (IC) to facilitate its precision administration.
METHODS
Single-dose plasma PKs of G-ABCD was studied in a rat IC model following intravenous administration at doses of 0.0625-10 mg/kg. Amphotericin B concentrations were determined and PK parameters were calculated based on the concentrations in plasma. The efficacy of G-ABCD was evaluated after single administration by the log reduction of CFU counts in kidney, liver, spleen and lung. The relationship between G-ABCD PK/PD index and log CFU reduction in kidney was calculated.
RESULTS
Following intravenous administration of G-ABCD at doses of 0.0625-10 mg/kg to rats, the maximum plasma concentration (C) was 0.05-0.82 mg/L and the area under the concentration-time curve from 0 to 24 h (AUC) was 0.50-5.29 mg h/L. G-ABCD showed potent antifungal activity against C. albicans C-13 with a maximum log CFU reduction of 2.1 in kidney. The mean AUC/MIC target of G-ABCD against C. albicans was 0.97 for stasis, 1.40 for 1-log kill and 3.34 for 2-log kill, and the mean C/MIC target was 0.063 for stasis, 0.097 for 1-log kill and 0.348 for 2-log kill.
CONCLUSIONS
The antifungal effect of G-ABCD was potent and correlated with AUC/MIC and C/MIC in this rat model of IC. The results of this study provide data for optimising G-ABCD dosing regimens and breakpoints for antifungals.
Topics: Amphotericin B; Animals; Antifungal Agents; Candida albicans; Candidiasis, Invasive; Microbial Sensitivity Tests; Rats
PubMed: 32890838
DOI: 10.1016/j.jgar.2020.08.019 -
Microbiology Spectrum Oct 2021The high morbidity and mortality of cryptococcal meningitis is due to the limited range of therapeutic options: only three classes of antifungal drugs are available...
The high morbidity and mortality of cryptococcal meningitis is due to the limited range of therapeutic options: only three classes of antifungal drugs are available (polyenes [amphotericin B], azoles [fluconazole], and pyrimidine analogues [flucytosine]). Fluconazole is the most widely used antifungal drug in sub-Saharan Africa, where cryptococcal meningitis is a major cause of death in patients infected with HIV. In this study, we found that exposure to fluconazole, even for short times (48 h) at subinhibitory concentrations, drove rapid adaptation of Cryptococcus neoformans serotype A strain H99 via the acquisition of different aneuploid chromosomes. These aneuploidies conferred heteroresistance to fluconazole. Importantly, most of the adaptors were cross-tolerant to flucytosine. Some of the aneuploid adaptors were not heteroresistant to fluconazole but were tolerant to amphotericin B. Thus, exposure to one antifungal drug class can promote adaptation to two antifungal drug classes, highlighting the plasticity of the C. neoformans genome and raising concerns about the rapid reduction in the range of treatment options for cryptococcal infections. Cryptococcosis is a globally distributed invasive fungal infection caused by infections with Cryptococcus neoformans or Cryptococcus gattii. Only three classes of therapeutic drugs are clinically available for treating cryptococcosis: polyenes (amphotericin B), azoles (fluconazole), and pyrimidine analogues (flucytosine). Fluconazole is the primary drug available in resource-limited countries. Aneuploidy is a genomic state due to the gain or loss of chromosomes. We found that C. neoformans rapidly adapted to fluconazole by acquiring diverse aneuploidies and that specific aneuploidies enabled improved growth of isolates susceptible (tolerance) to amphotericin B and/or cross-tolerance to both fluconazole and flucytosine. Therefore, aneuploidy is an underlying mechanism of drug tolerance that not only arises rapidly during growth in fluconazole but can also confer tolerance to other antifungal drugs without prior exposure to those drugs. Resistant isolates have high MICs, and all cells grow similarly in medium with the drug, while tolerant isolates test as susceptible and grow slowly at drug concentrations above the MIC.
Topics: Adaptation, Physiological; Amphotericin B; Aneuploidy; Antifungal Agents; Cryptococcosis; Cryptococcus gattii; Cryptococcus neoformans; Drug Resistance, Fungal; Fluconazole; Flucytosine; Humans; Microbial Sensitivity Tests; Serogroup
PubMed: 34585947
DOI: 10.1128/Spectrum.00723-21