Fitness Trade-offs Restrict the Evolution of Resistance to Amphotericin B

Vincent, Benjamin; Lancaster, Alex K.; Scherz-Shouval, Ruth; Whitesell, Luke; Lindquist, Susan

doi:10.1371/journal.pbio.1001692

Cited by 270 publications

(276 citation statements)

References 60 publications

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“…In fact, in a systematic investigation to define genes whose inactivation confers AmB resistance, it was found that the MIC for AmB against C. albicans was increased more than 3-fold by the deletion of ERG2 or ERG6 or of ERG3 and ERG11 together, all of which are involved in the ergosterol biosynthetic pathway (55). Vincent et al have also reported that the evolution of ERG2/erg2⌬ heterozygotes of AmB-R C. albicans strains requires the presence of Hog1 or calcineurin or high levels of the Hsp90 molecular chaperone (55). However, the changes made in the AmB-R phenotype by the deletion of the ERG genes involve substantial fitness costs because the resistant strains exhibited drastically reduced tolerance not only of oxidative stresses but also of other external stresses such as high temperatures, killing by neutrophils, impairment in the filamentation process, and tissue invasion (55).…”

Section: The Development Of Amb Resistance In Eukaryotic Pathogensmentioning

confidence: 99%

“…Vincent et al have also reported that the evolution of ERG2/erg2⌬ heterozygotes of AmB-R C. albicans strains requires the presence of Hog1 or calcineurin or high levels of the Hsp90 molecular chaperone (55). However, the changes made in the AmB-R phenotype by the deletion of the ERG genes involve substantial fitness costs because the resistant strains exhibited drastically reduced tolerance not only of oxidative stresses but also of other external stresses such as high temperatures, killing by neutrophils, impairment in the filamentation process, and tissue invasion (55). Interestingly, Hsp90, by repressing Ras1-PKA signaling, is known to regulate a key temperature-dependent morphogenetic transition from yeast to filamentous growth that is crucial for virulence in fungal cells (56).…”

Section: The Development Of Amb Resistance In Eukaryotic Pathogensmentioning

confidence: 99%

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The Role of Signaling via Aqueous Pore Formation in Resistance Responses to Amphotericin B

Cohen

2016

Antimicrob Agents Chemother

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Drug resistance studies have played an important role in the validation of antibiotic targets. In the case of the polyene antibiotic amphotericin B (AmB), such studies have demonstrated the essential role that depletion of ergosterol plays in the development of AmB-resistant (AmB-R) organisms. However, AmB-R strains also occur in fungi and parasitic protozoa that maintain a normal level of ergosterol at the plasma membrane. Here, I review evidence that shows not only that there is increased protection against the deleterious consequences of AmB-induced ion leakage across the membrane in these resistant pathogens but also that a set of events are activated that block the cell signaling responses that trigger the oxidative damage produced by the antibiotic. Such signaling events appear to be the consequence of a membrane-thinning effect that is exerted upon lipid-anchored Ras proteins by the aqueous pores formed by AmB. A similar membrane disturbance effect may also explain the activity of AmB on mammalian cells containing Toll-like receptors. These resistance mechanisms expand our current understanding of the role that the formation of AmB aqueous pores plays in triggering signal transduction responses in both pathogens and host immune cells.

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Section: The Development Of Amb Resistance In Eukaryotic Pathogensmentioning

confidence: 99%

Section: The Development Of Amb Resistance In Eukaryotic Pathogensmentioning

confidence: 99%

The Role of Signaling via Aqueous Pore Formation in Resistance Responses to Amphotericin B

Cohen

2016

Antimicrob Agents Chemother

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“…This buffering capacity allows it to modulate the manifestation of preexisting and newly acquired genetic variation within heterogeneous populations of cells, and even whole organisms, thereby dramatically expanding the range of phenotypes on which selection can act (1, 2, 5-7). As a dramatic, therapeutically relevant example, we have shown that this HSP90 buffer enables fungal pathogens spanning ∼1 billion years of evolution to evolve and maintain resistance to every major antifungal in general use (8,9). Now we ask whether HSP90 might serve a similar role in buffering the molecular and genetic heterogeneity present in human tumors and whether low-level inhibition might limit the emergence of drug resistance.…”

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confidence: 99%

HSP90 empowers evolution of resistance to hormonal therapy in human breast cancer models

Whitesell

Santagata

Mendillo

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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111

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The efficacy of hormonal therapies for advanced estrogen receptorpositive breast cancers is limited by the nearly inevitable development of acquired resistance. Efforts to block the emergence of resistance have met with limited success, largely because the mechanisms underlying it are so varied and complex. Here, we investigate a new strategy aimed at the very processes by which cancers evolve resistance. From yeast to vertebrates, heat shock protein 90 (HSP90) plays a unique role among molecular chaperones by promoting the evolution of heritable new traits. It does so by regulating the folding of a diverse portfolio of metastable client proteins, many of which mediate adaptive responses that allow organisms to adapt and thrive in the face of diverse challenges, including those posed by drugs. Guided by our previous work in pathogenic fungi, in which very modest HSP90 inhibition impairs resistance to mechanistically diverse antifungals, we examined the effect of similarly modest HSP90 inhibition on the emergence of resistance to antiestrogens in breast cancer models. Even though this degree of inhibition fell below the threshold for proteotoxic activation of the heat-shock response and had no overt anticancer activity on its own, it dramatically impaired the emergence of resistance to hormone antagonists both in cell culture and in mice. Our findings strongly support the clinical testing of combined hormone antagonist-low-level HSP90 inhibitor regimens in the treatment of metastatic estrogen receptor-positive breast cancer. At a broader level, they also provide promising proof of principle for a generalizable strategy to combat the pervasive problem of rapidly emerging resistance to molecularly targeted therapeutics.estrogen receptor | antiestrogen | drug resistance | tumor progression | tamoxifen D rastically limiting the efficacy of targeted therapeutics, the emergence of drug resistance in advanced cancers remains nearly inevitable. From yeast to vertebrates, the molecular chaperone heat shock protein 90 (HSP90) allows organisms to adapt and thrive in the face of diverse challenges, including those posed by drugs and environmental stressors (1, 2). It does so by regulating the folding of a highly diverse portfolio of metastable client proteins, many mediating adaptive responses (3, 4).However, this role for HSP90 in adaptation is greatly magnified by its ability to promote the evolution of heritable new traits. To buffer the proteome against unexpected environmental challenges, HSP90 is present in large excess under normal circumstances. This buffering capacity allows it to modulate the manifestation of preexisting and newly acquired genetic variation within heterogeneous populations of cells, and even whole organisms, thereby dramatically expanding the range of phenotypes on which selection can act (1, 2, 5-7). As a dramatic, therapeutically relevant example, we have shown that this HSP90 buffer enables fungal pathogens spanning ∼1 billion years of evolution to evolve and maintain resistance to every major a...

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“…Fungal pathogens can become resistant by replacing ergosterol with alternative sterols that do not bind polyenes. However, this results in diminished virulence and has not posed a serious clinical problem (Vincent et al, 2013).…”

Section: Recent Insights Into Biological Activities Of Polyene Macrolmentioning

confidence: 99%

Polyene macrolide biosynthesis in streptomycetes and related bacteria: recent advances from genome sequencing and experimental studies

Caffrey

Poire

Sheehan

et al. 2016

Appl Microbiol Biotechnol

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Fitness Trade-offs Restrict the Evolution of Resistance to Amphotericin B

Abstract: The rarity of clinical drug resistance to the antifungal amphotericin B is explained by the extreme costs that resistance mutations impose upon stress responses and virulence factors.

Cited by 270 publications

References 60 publications

The Role of Signaling via Aqueous Pore Formation in Resistance Responses to Amphotericin B

The Role of Signaling via Aqueous Pore Formation in Resistance Responses to Amphotericin B

HSP90 empowers evolution of resistance to hormonal therapy in human breast cancer models

Polyene macrolide biosynthesis in streptomycetes and related bacteria: recent advances from genome sequencing and experimental studies

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