Amphotericin B: Polyene Resistance Mechanisms

2009 ◽  
pp. 295-305 ◽  
Author(s):  
Elizabeth M. O'Shaughnessy ◽  
Caron A. Lyman ◽  
Thomas J. Walsh
Keyword(s):  
Amphotericin B ◽  
Resistance Mechanisms

scholarly journals Synthetic Lethality Screening Identifies FDA-Approved Drugs that Overcome ATP7B-Mediated Tolerance of Tumor Cells to Cisplatin

Cancers ◽  
2020 ◽  
Vol 12 (3) ◽  
pp. 608 ◽  
Author(s):  
Marta Mariniello ◽  
Raffaella Petruzzelli ◽  
Luca G. Wanderlingh ◽  
Raffaele La Montagna ◽  
Annamaria Carissimo ◽  
...  
Keyword(s):  
Amphotericin B ◽  
Therapeutic Potential ◽  
Synthetic Lethality ◽  
Resistance Mechanisms ◽  
Ovarian Cancer Cells ◽  
Tumor Resistance ◽  
Development Of Resistance ◽  
Wide Range ◽  
Important Challenge ◽  
Approved Drugs

Tumor resistance to chemotherapy represents an important challenge in modern oncology. Although platinum (Pt)-based drugs have demonstrated excellent therapeutic potential, their effectiveness in a wide range of tumors is limited by the development of resistance mechanisms. One of these mechanisms includes increased cisplatin sequestration/efflux by the copper-transporting ATPase, ATP7B. However, targeting ATP7B to reduce Pt tolerance in tumors could represent a serious risk because suppression of ATP7B might compromise copper homeostasis, as happens in Wilson disease. To circumvent ATP7B-mediated Pt tolerance we employed a high-throughput screen (HTS) of an FDA/EMA-approved drug library to detect safe therapeutic molecules that promote cisplatin toxicity in the IGROV-CP20 ovarian carcinoma cells, whose resistance significantly relies on ATP7B. Using a synthetic lethality approach, we identified and validated three hits (Tranilast, Telmisartan, and Amphotericin B) that reduced cisplatin resistance. All three drugs induced Pt-mediated DNA damage and inhibited either expression or trafficking of ATP7B in a tumor-specific manner. Global transcriptome analyses showed that Tranilast and Amphotericin B affect expression of genes operating in several pathways that confer tolerance to cisplatin. In the case of Tranilast, these comprised key Pt-transporting proteins, including ATOX1, whose suppression affected ability of ATP7B to traffic in response to cisplatin. In summary, our findings reveal Tranilast, Telmisartan, and Amphotericin B as effective drugs that selectively promote cisplatin toxicity in Pt-resistant ovarian cancer cells and underscore the efficiency of HTS strategy for identification of biosafe compounds, which might be rapidly repurposed to overcome resistance of tumors to Pt-based chemotherapy.

Amphotericin B: Polyene Resistance Mechanisms

2017 ◽  
pp. 387-395 ◽  
Author(s):  
Matthew McCarthy ◽  
Elizabeth M. O’Shaughnessy ◽  
Thomas J. Walsh
Keyword(s):  
Amphotericin B ◽  
Resistance Mechanisms

scholarly journals Multicenter Evaluation of MIC Distributions for Epidemiologic Cutoff Value Definition To Detect Amphotericin B, Posaconazole, and Itraconazole Resistance among the Most Clinically Relevant Species of Mucorales

2015 ◽  
Vol 59 (3) ◽  
pp. 1745-1750 ◽  
Author(s):  
A. Espinel-Ingroff ◽  
A. Chakrabarti ◽  
A. Chowdhary ◽  
S. Cordoba ◽  
E. Dannaoui ◽  
...  
Keyword(s):  
Amphotericin B ◽  
Acquired Resistance ◽  
The United States ◽  
Resistance Mechanisms ◽  
Wild Type ◽  
Content Type ◽  
Syncephalastrum Racemosum ◽  
Mucor Indicus ◽  
Clinical Breakpoints ◽  
Lichtheimia Corymbifera

ABSTRACTClinical breakpoints (CBPs) have not been established for theMucoralesand any antifungal agent. In lieu of CBPs, epidemiologic cutoff values (ECVs) are proposed for amphotericin B, posaconazole, and itraconazole and fourMucoralesspecies. Wild-type (WT) MIC distributions (organisms in a species-drug combination with no detectable acquired resistance mechanisms) were defined with available pooled CLSI MICs from 14 laboratories (Argentina, Australia, Canada, Europe, India, Mexico, and the United States) as follows: 10Apophysomyces variabilis, 32Cunninghamella bertholletiae, 136Lichtheimia corymbifera, 10Mucor indicus, 123M. circinelloides, 19M. ramosissimus, 349Rhizopus arrhizus, 146R. microsporus, 33Rhizomucor pusillus, and 36Syncephalastrum racemosumisolates. CLSI broth microdilution MICs were aggregated for the analyses. ECVs comprising ≥95% and ≥97.5% of the modeled populations were as follows: amphotericin B ECVs forL. corymbiferawere 1 and 2 μg/ml, those forM. circinelloideswere 1 and 2 μg/ml, those forR. arrhizuswere 2 and 4 μg/ml, and those forR. microsporuswere 2 and 2 μg/ml, respectively; posaconazole ECVs forL. corymbiferawere 1 and 2, those forM. circinelloideswere 4 and 4, those forR. arrhizuswere 1 and 2, and those forR. microsporuswere 1 and 2, respectively; both itraconazole ECVs forR. arrhizuswere 2 μg/ml. ECVs may aid in detecting emerging resistance or isolates with reduced susceptibility (non-WT MICs) to the agents evaluated.

scholarly journals In VitroActivity of ASP2397 against Aspergillus Isolates with or without Acquired Azole Resistance Mechanisms

2015 ◽  
Vol 60 (1) ◽  
pp. 532-536 ◽  
Author(s):  
Maiken Cavling Arendrup ◽  
Rasmus Hare Jensen ◽  
Manuel Cuenca-Estrella
Keyword(s):  
Amphotericin B ◽  
Target Gene ◽  
Antifungal Agents ◽  
Susceptibility Testing ◽  
Resistance Mechanisms ◽  
Azole Resistance ◽  
Wild Type ◽  
Resistance Mutations ◽  
Content Type

ABSTRACTASP2397 is a new compound with a novel and as-yet-unknown target different from that of licensed antifungal agents. It has activity againstAspergillusandCandida glabrata. We compared itsin vitroactivity against wild-type and azole-resistantA. fumigatusandA. terreusisolates with that of amphotericin B, itraconazole, posaconazole, and voriconazole. Thirty-four isolates, including 4 wild-typeA. fumigatusisolates, 24A. fumigatusisolates with alterations in CYP51A TR/L98H (5 isolates), M220 (9 isolates), G54 (9 isolates), and HapE (1 isolate), andA. terreusisolates (2 wild-type isolates and 1 isolate with an M217I CYP51A alteration), were analyzed. EUCAST E.Def 9.2 and CLSI M38-A2 MIC susceptibility testing was performed. ASP2397 MIC50values (in milligrams per liter, with MIC ranges in parentheses) determined by EUCAST and CLSI were 0.5 (0.25 to 1) and 0.25 (0.06 to 0.25) againstA. fumigatusCYP51A wild-type isolates and were similarly 0.5 (0.125 to >4) and 0.125 (0.06 to >4) against azole-resistantA. fumigatusisolates, respectively. These values were comparable to those for amphotericin B, which were 0.25 (0.125 to 0.5) and 0.25 (0.125 to 0.25) against wild-type isolates and 0.25 (0.125 to 1) and 0.25 (0.125 to 1) against isolates with azole resistance mechanisms, respectively. In contrast, MICs for the azole compounds were elevated and highest for itraconazole: >4 (1 to >4) and 4 (0.5 to >4) against isolates with azole resistance mechanisms compared to 0.125 (0.125 to 0.25) and 0.125 (0.06 to 0.25) against wild-type isolates, respectively. ASP2397 was active againstA. terreusCYP51A wild-type isolates (MIC 0.5 to 1), whereas MICs of both azole and ASP2397 were elevated for the mutant isolate. ASP2397 displayedin vitroactivity againstA. fumigatusandA. terreusisolates which was independent of the presence or absence of azole target gene resistance mutations inA. fumigatus. The findings are promising at a time when azole-resistantA. fumigatusis emerging globally.

scholarly journals Chemogenomic Profiling of Antileishmanial Efficacy and Resistance in the Related Kinetoplastid Parasite Trypanosoma brucei

2019 ◽  
Vol 63 (8) ◽  
Author(s):  
Clare F. Collett ◽  
Carl Kitson ◽  
Nicola Baker ◽  
Heather B. Steele-Stallard ◽  
Marie-Victoire Santrot ◽  
...  
Keyword(s):  
Amphotericin B ◽  
Trypanosoma Brucei ◽  
Mode Of Action ◽  
Drug Efficacy ◽  
Resistance Mechanisms ◽  
Major Facilitator Superfamily ◽  
Drug Uptake ◽  
Cross Resistance ◽  
Content Type ◽  
Kinetoplastid Parasite

ABSTRACT The arsenal of drugs used to treat leishmaniasis, caused by Leishmania spp., is limited and beset by toxicity and emergent resistance. Furthermore, our understanding of drug mode of action and potential routes to resistance is limited. Forward genetic approaches have revolutionized our understanding of drug mode of action in the related kinetoplastid parasite Trypanosoma brucei. Therefore, we screened our genome-scale T. brucei RNA interference (RNAi) library against the current antileishmanial drugs sodium stibogluconate (antimonial), paromomycin, miltefosine, and amphotericin B. Identification of T. brucei orthologues of the known Leishmania antimonial and miltefosine plasma membrane transporters effectively validated our approach, while a cohort of 42 novel drug efficacy determinants provides new insights and serves as a resource. Follow-up analyses revealed the antimonial selectivity of the aquaglyceroporin TbAQP3. A lysosomal major facilitator superfamily transporter contributes to paromomycin-aminoglycoside efficacy. The vesicle-associated membrane protein TbVAMP7B and a flippase contribute to amphotericin B and miltefosine action and are potential cross-resistance determinants. Finally, multiple phospholipid-transporting flippases, including the T. brucei orthologue of the Leishmania miltefosine transporter, a putative β-subunit/CDC50 cofactor, and additional membrane-associated hits, affect amphotericin B efficacy, providing new insights into mechanisms of drug uptake and action. The findings from this orthology-based chemogenomic profiling approach substantially advance our understanding of antileishmanial drug action and potential resistance mechanisms and should facilitate the development of improved therapies as well as surveillance for drug-resistant parasites.

scholarly journals Amphotericin B and Other Polyenes—Discovery, Clinical Use, Mode of Action and Drug Resistance

2020 ◽  
Vol 6 (4) ◽  
pp. 321
Author(s):  
Hans Carolus ◽  
Siebe Pierson ◽  
Katrien Lagrou ◽  
Patrick Van Dijck
Keyword(s):  
Drug Resistance ◽  
Amphotericin B ◽  
Mode Of Action ◽  
Fungal Infections ◽  
Resistance Mechanisms ◽  
Antifungal Drugs ◽  
Clinical Use ◽  
Candida Auris ◽  
Resistance Development ◽  
Resistant Species

Although polyenes were the first broad spectrum antifungal drugs on the market, after 70 years they are still the gold standard to treat a variety of fungal infections. Polyenes such as amphotericin B have a controversial image. They are the antifungal drug class with the broadest spectrum, resistance development is still relatively rare and fungicidal properties are extensive. Yet, they come with a significant host toxicity that limits their use. Relatively recently, the mode of action of polyenes has been revised, new mechanisms of drug resistance were discovered and emergent polyene resistant species such as Candida auris entered the picture. This review provides a short description of the history and clinical use of polyenes, and focusses on the ongoing debate concerning their mode of action, the diversity of resistance mechanisms discovered to date and the most recent trends in polyene resistance development.

Unmasking the Amphotericin B Resistance Mechanisms in Candida haemulonii Species Complex

2020 ◽  
Vol 6 (5) ◽  
pp. 1273-1282 ◽  
Author(s):  
Laura N. Silva ◽  
Simone S. C. Oliveira ◽  
Lucas B. Magalhães ◽  
Valter V. Andrade Neto ◽  
Eduardo C. Torres-Santos ◽  
...  
Keyword(s):  
Amphotericin B ◽  
Species Complex ◽  
Resistance Mechanisms ◽  
Candida Haemulonii

scholarly journals In Vitro Susceptibility of Field Isolates of Leishmania donovani to Miltefosine and Amphotericin B: Correlation with Sodium Antimony Gluconate Susceptibility and Implications for Treatment in Areas of Endemicity

2008 ◽  
Vol 53 (2) ◽  
pp. 835-838 ◽  
Author(s):  
Dhiraj Kumar ◽  
Arpita Kulshrestha ◽  
Ruchi Singh ◽  
Poonam Salotra
Keyword(s):  
Amphotericin B ◽  
Gene Expression Analysis ◽  
Leishmania Donovani ◽  
Resistance Mechanisms ◽  
Cross Resistance ◽  
In Vitro Susceptibility ◽  
Field Isolates ◽  
Antimony Resistance ◽  
Sodium Antimony Gluconate

ABSTRACT Indian Leishmania donovani isolates (n = 19) from regional zones representing various levels of antimony resistance displayed significantly (P < 0.01) correlated results with respect to in vitro susceptibility to the antileishmanial drugs sodium antimony gluconate, amphotericin B, and Miltefosine, raising the possibility of cross-resistance mechanisms operating in the field isolates. The results of gene expression analysis of LdMT and LdRos3 were suggestive of alternate mechanisms of Miltefosine susceptibility in the isolates.

scholarly journals Wild-Type MIC Distributions and Epidemiological Cutoff Values for Amphotericin B and Aspergillus spp. for the CLSI Broth Microdilution Method (M38-A2 Document)

2011 ◽  
Vol 55 (11) ◽  
pp. 5150-5154 ◽  
Author(s):  
A. Espinel-Ingroff ◽  
M. Cuenca-Estrella ◽  
A. Fothergill ◽  
J. Fuller ◽  
M. Ghannoum ◽  
...  
Keyword(s):  
Amphotericin B ◽  
Acquired Resistance ◽  
The United States ◽  
Resistance Mechanisms ◽  
Broth Microdilution ◽  
Wild Type ◽  
Content Type ◽  
Microdilution Method ◽  
Cutoff Values ◽  
Broth Microdilution Method

ABSTRACTAlthough clinical breakpoints have not been established for mold testing, epidemiological cutoff values (ECVs) are available forAspergillusspp. versus the triazoles and caspofungin. Wild-type (WT) MIC distributions (organisms in a species-drug combination with no acquired resistance mechanisms) were defined in order to establish ECVs for sixAspergillusspp. and amphotericin B. Two sets (CLSI/EUCAST broth microdilution) of available MICs were evaluated: those forA. fumigatus(3,988/833),A. flavus(793/194),A. nidulans(184/69),A. niger(673/140),A. terreus(545/266), andA. versicolor(135/22). Three sets of data were analyzed: (i) CLSI data gathered in eight independent laboratories in Canada, Europe, and the United States; (ii) EUCAST data from a single laboratory; and (iii) the combined CLSI and EUCAST data. ECVs, expressed in μg/ml, that captured 95%, 97.5%, and 99% of the modeled wild-type population (CLSI and combined data) were as follows: forA. fumigatus, 2, 2, and 4; forA. flavus, 2, 4, and 4; forA. nidulans, 4, 4, and 4; forA. niger, 2, 2, and 2; forA. terreus, 4, 4, and 8; and forA. versicolor, 2, 2, and 2. Similar to the case for the triazoles and caspofungin, amphotericin B ECVs may aid in the detection of strains with acquired mechanisms of resistance to this agent.

scholarly journals Synthetic lethality screening identifies FDA-approved drugs that overcome ATP7B-mediated tolerance of tumor cells to cisplatin

2019 ◽  
Author(s):  
Marta Mariniello ◽  
Raffaella Petruzzelli ◽  
Luca G. Wanderlingh ◽  
Raffaele La Montagna ◽  
Annamaria Carissimo ◽  
...  
Keyword(s):  
Amphotericin B ◽  
Therapeutic Potential ◽  
Synthetic Lethality ◽  
Rapid Development ◽  
Resistance Mechanisms ◽  
Tumor Resistance ◽  
Ovarian Carcinoma Cell Line ◽  
Development Of Resistance ◽  
Wide Range ◽  
Approved Drugs

ABSTRACTTumor resistance to chemotherapy represents an important challenge in modern oncology. Although platinum (Pt)-based drugs have demonstrated excellent therapeutic potential, their effectiveness in a wide range of tumors is limited by the development of resistance mechanisms. One of these mechanisms includes increased cisplatin sequestration/efflux by the copper-transporting ATPase, ATP7B. However, targeting ATP7B to reduce Pt tolerance in tumors could represent a serious risk because suppression of ATP7B might compromise copper homeostasis, as happens in Wilson disease.To circumvent ATP7B-mediated Pt tolerance we employed a high-throughput screen (HTS) of an FDA/EMA-approved drug library to detect safe therapeutic molecules that promote cisplatin toxicity in the resistant ovarian carcinoma cell line IGROV-CP20. Using a synthetic lethality approach we identified and validated three hits (Tranilast, Telmisartan and Amphotericin B) that could reduce cisplatin resistance. All three drugs induced Pt-mediated DNA damage and inhibited either expression or trafficking of ATP7B in a tumor-specific manner. Global transcriptome analyses showed that Tranilast and Amphotericin B affect expression of genes operating in several pathways that confer tolerance to cisplatin. In the case of Tranilast, these included key molecular players operating in the distribution of platinum to different intracellular compartments. In particular, Tranilast was found to suppress ATOX1 and, as a consequence, ATOX1-mediated trafficking of ATP7B in response to cisplatin.Considering the well-known safety profiles of Tranilast, Telmisartan and Amphotericin B, these drugs emerge as potential candidates that might be used for the rapid development of new therapeutic strategies to overcome resistance of tumors to Pt-based chemotherapy.

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