C3-OH of Amphotericin B Plays an Important Role in Ion Conductance

Davis, Stephen; Ripa, Lisa A. Della; Hu, Lingbowei; Cioffi, Alexander G.; Pogorelov, Taras V.; Rienstra, Chad M.; Burke, Martin D.

doi:10.1021/jacs.5b05766

Cited by 16 publications

(11 citation statements)

References 36 publications

(21 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…These observations and the presence of significant amounts of various ergosta-type and cholesta-type sterols in mutant C. glabrata cells suggest that at least some of these sterols can also maintain fungal membrane fluidity and are also sensitive to removal by the extramembranous AMB sponge. It will be interesting to see how these mutant strains respond to other derivatives of AMB that have recently been synthesized to overcome the problem of the toxicity of AMB to mammalian cells (9,34,35).…”

Section: Discussionmentioning

confidence: 99%

ERG6 and ERG2 Are Major Targets Conferring Reduced Susceptibility to Amphotericin B in Clinical Candida glabrata Isolates in Kuwait

Ahmad

Joseph

Parker

et al. 2019

Antimicrob Agents Chemother

View full text Add to dashboard Cite

Candida glabrata is intrinsically less susceptible to azoles, and resistance to echinocandins and reduced susceptibility (RS) to amphotericin B (AMB) have also been detected. The molecular mechanisms of RS to AMB were investigated in C. glabrata strains in Kuwait by sequence analyses of genes involved in ergosterol biosynthesis. A total of 1,646 C. glabrata isolates were tested by Etest, and results for 12 selected isolates were confirmed by reference broth microdilution. PCR sequencing of three genes (ERG2, ERG6, and ERG11) was performed for all isolates with RS to AMB (RS-AMB isolates) and 5 selected wild-type C. glabrata isolates by using gene-specific primers. The total cell sterol content was analyzed by gas chromatography-mass spectrometry. The phylogenetic relationship among the isolates was investigated by multilocus sequence typing. Wild-type isolates contained only synonymous mutations in ERG2, ERG6, or ERG11, and the total sterol content was similar to that of the reference strains. A nonsynonymous ERG6 mutation (AGA48AAA, R48K) was found in both RS-AMB and wild-type isolates. Four RS-AMB isolates contained novel nonsense mutations at Trp286, Tyr192, and Leu341, and 2 isolates contained a nonsynonymous mutation in ERG6 (V126F or C198F); and the sterol content of these isolates was consistent with ERG6 deficiency. Two other RS-AMB isolates contained a novel nonsynonymous ERG2 mutation (G119S or G122S), and their sterol content was consistent with ERG2 deficiency. Of 8 RS-AMB isolates, 1 fluconazole-resistant isolate also contained nonsynonymous Y141H plus L381M mutations, while 7 isolates contained only synonymous mutations in ERG11. All isolates with ERG6, ERG2, and ERG11 mutations were genotypically distinct strains. Our data show that ERG6 and ERG2 are major targets conferring RS-AMB in clinical C. glabrata isolates.

show abstract

Section: Discussionmentioning

confidence: 99%

ERG6 and ERG2 Are Major Targets Conferring Reduced Susceptibility to Amphotericin B in Clinical Candida glabrata Isolates in Kuwait

Ahmad

Joseph

Parker

et al. 2019

Antimicrob Agents Chemother

View full text Add to dashboard Cite

show abstract

“…Moreover, a recent study described that the interactions of AMB with biomembranes are managed by the molecular organization of AMB ( Starzyk et al, 2014 ). AMB self-associates to dimeric structures; AMB dimers can further assemble into tetramers, which induce the formation of transmembrane ion channels, impairing the electrophysiological homeostasis of a living cell ( Starzyk et al, 2014 ; Davis et al, 2015 ). Considering all these findings, it is possible that CST binds to AMB molecules and accelerates the assembly of AMB tetramers, thus inducing pore formation on fungal cell membranes, also triggering a strong cell stress response, which is typical of AMB action.…”

Section: Discussionmentioning

confidence: 99%

Unveiling the Synergistic Interaction Between Liposomal Amphotericin B and Colistin

et al. 2016

View full text Add to dashboard Cite

Patients with multiple comorbidities are often administered simultaneously or sequentially antifungals and antibacterial agents, without full knowledge of the consequences of drug interactions. Considering the clinical relevance of liposomal amphotericin B (L-AMB), the association between L-AMB and six antibacterial agents was evaluated against four clinical isolates and one type strain of Candida spp. and two clinical isolates and one type strain of Aspergillus fumigatus. In order to evaluate such combined effects, the minimal inhibitory concentration (MIC) of L-AMB was determined in the presence of 0.5-, 1-, 2-, and 4-fold peak plasma concentrations of each of the antibacterial drugs. Since the L-AMB/colistin (CST) association was the most synergic, viability assays were performed and the physiological status induced by this association was characterized. In addition, computational molecular dynamics studies were also performed in order to clarify the molecular interaction. The maximum synergistic effect with all antibacterial agents, except CST, was reached at fourfold the usual peak plasma concentrations, resulting in 2-to 8-fold L-AMB MIC reduction for Candida and 2-to 16-fold for Aspergillus. For CST, the greatest synergism was registered at peak plasma concentration (3 mg/L), with 4-to 8-fold L-AMB MIC reduction for Candida and 16-to 32-fold for Aspergillus. L-AMB at subinhibitory concentration (0.125 mg/L) combined with CST 3 mg/L resulted in: a decrease of fungal cell viability; an increase of cell membrane permeability; an increase of cellular metabolic activity soon after 1 h of exposure, which decreased until 24 h; and an increase of ROS production up to 24 h. From the molecular dynamics studies, AMB and CST molecules shown a propensity to form a stable molecular complex in solution, conferring a recognition and binding added value for membrane intercalation. Our results demonstrate that CST interacts synergistically with L-AMB, forming a stable complex, which promotes the fungicidal activity of L-AMB at low concentration.

show abstract

“…除利用基因工程改造策略外, 多个课题组还利用化学手段获得了多种多元醇区域的结构改造衍生物 [29,47,48] . 与上述衍生物的药理性质相似, 化学方法获得的衍生物的抗真菌活性与溶血毒性同样存在不同程度的降低.…”

Section: 原酶5(er5)结构域成功获得了制霉菌素A1的七烯unclassified

Structural modifications and yield improvements of polyene macrolide antibiotics

Qi¹,

LinQuan²

2017

Chin. Sci. Bull.

View full text Add to dashboard Cite

C3-OH of Amphotericin B Plays an Important Role in Ion Conductance

Cited by 16 publications

References 36 publications

ERG6 and ERG2 Are Major Targets Conferring Reduced Susceptibility to Amphotericin B in Clinical Candida glabrata Isolates in Kuwait

ERG6 and ERG2 Are Major Targets Conferring Reduced Susceptibility to Amphotericin B in Clinical Candida glabrata Isolates in Kuwait

Unveiling the Synergistic Interaction Between Liposomal Amphotericin B and Colistin

Structural modifications and yield improvements of polyene macrolide antibiotics

Contact Info

Product

Resources

About