Quantitative structure-activity relationships in amphotericin B derivatives

Chéron, Monique; Cybulska, Barbara; Mazerski, Jan; Grzybowska, Jolanta; Czerwiński, A.; Borowski, Edward

doi:10.1016/0006-2952(88)90168-2

Cited by 131 publications

(101 citation statements)

References 13 publications

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“…It should be also noted that in the context of the proposed AmB channel model, the nature of the substitutions in PAmE and SAmE (namely the elimination of a carboxyl group charge and the introduction of a bulky substituent to the amino group) can also be seen as lowering the stabilization of the channel and, consequently, as improving the selective toxicity of both compounds. However, earlier experiments in our laboratory have also shown that simply blocking both ionizable groups of the polar head is not sufficient to largely improve the selectivity [52,59].…”

Section: Accepted M Manuscriptmentioning

confidence: 84%

Influence of a lipid bilayer on the conformational behavior of amphotericin B derivatives — A molecular dynamics study

Neumann

Borowski

Bagiński

2009

Biophysical Chemistry

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. Influence of a lipid bilayer on the conformational behavior of amphotericin B derivatives -a molecular dynamics study. Biophysical Chemistry, Elsevier, 2009, 141 (1) This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Author to whom the correspondence should be addressed. A C C E P T E D M A N U S C R I P T ACCEPTED MANUSCRIPT A C C E P T E D M A N U S C R I P T ACCEPTED MANUSCRIPT A C C E P T E D M A N U S C R I P T ACCEPTED MANUSCRIPT3 AbstractAmphotericin B (AmB) is an effective but very toxic antifungal antibiotic. In our laboratory a series of AmB derivatives of improved selectivity of action was synthesized and tested. To understand molecular basis of this improvement, comparative conformational studies of amphotericin B and its two more selective derivatives were carried out in an aqueous solution and in a lipid membrane. These molecular simulation studies revealed that within a membrane environment the conformational behavior of the derivatives differs significantly from the one observed for the parent molecule. Possible reasons for such a difference are analyzed. Furthermore, we hypothesize that the observed conformational transition within the polar head of AmB derivatives may lead to destabilization of antibioticinduced transmembrane channels. Consequently, the selective toxicity of the derivatives should increase as ergosterol-rich liquid-ordered domains are more rigid and conformationally ordered than their cholesterol-containing counterparts, and as such may better support less stable channel structure.

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Section: Accepted M Manuscriptmentioning

confidence: 84%

Influence of a lipid bilayer on the conformational behavior of amphotericin B derivatives — A molecular dynamics study

Neumann

Borowski

Bagiński

2009

Biophysical Chemistry

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“…by N-amino acylation [29,30]; the degree of the proton affinity of the amino group does not influence the selectivity of the interaction with sterols [31];…”

Section: Discussionmentioning

confidence: 99%

“…• there is no evidence that other functional groups of AmB play an essential role in its activity; however, esterification or amidation of the carboxyl group slightly improves selective affinity of the antibiotic in regard to ergosterol as compared to cholesterol containing membranes [31];…”

Section: Discussionmentioning

confidence: 99%

Molecular modeling of amphotericin B–ergosterol primary complex in water II

Baran

Borowski²,

Mazerski³

2009

Biophysical Chemistry

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The work presented is a part of our continual study on the behavior of the polyene macrolide antibiotic amphotericin B (AmB) complexes with sterols on the molecular level. In contrast to the previously researched AmB-ergosterol binary complex, the AmB-ergosterol-AmB aggregates simulated of 2:1 stoichiometry retain significantly higher stability and relatively rigid, "sandwich" geometry. Van der Waals forces with a considerable share of the electrostatic interactions are responsible for such behavior. System of the intermolecular hydrogen bonds also seems to be of notable importance for the complex's structure preservation. The most energetically favored geometries match fairly close the geometric criteria and the network of interactions postulated in the contemporary hypothetical and computational models of antibiotic-sterol complexes. On the basis of works previously published and the present study novel hypotheses on the AmB selectivity towards sterols varying in chemical structure and on the possible mechanisms of channel structure formation were presented.A

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“…Therefore, developing polyene derivatives with inherent reduced toxicity draws the attention of many scholars. Chemical modification has shown that suppression of charge on the exocyclic carboxyl group reduces toxicity and improves antifungal specificity [9]. In the study of amphotericin B, chemically synthesized decarboxyl amphotericin B has lower toxicity than amphotericin B.…”

Section: Introductionmentioning

confidence: 99%

“…In the study of amphotericin B, chemically synthesized decarboxyl amphotericin B has lower toxicity than amphotericin B. Modification of the exocyclic carboxyl group of amphotericin B is known to bring about a substantial reduction in its toxicity [9,10]. When the polyene interacts with membrane sterols, the carboxyl group is contributed to an extensive network of hydrogen bonds that involves the mycosamine amino group, a water molecule, and the sterol hydroxyl group [10,11].…”

Section: Introductionmentioning

confidence: 99%

The pH Shift and Precursor Feeding Strategy in a Low-Toxicity FR-008/Candicidin Derivative CS103 Fermentation Bioprocess by a Mutant of Streptomyces sp. FR-008

Mao

Wang

Zhang

et al. 2009

Appl Biochem Biotechnol

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CS103, the novel derivative of polyene macrolides antibiotic FR-008/candicidin with lower toxicity has been isolated from the culture mycelia of the mutant of Streptomyces sp. FR-008, with targeted deletions of the fscP cytochrome P450 gene from its chromosome. To enhance biosynthesis of CS103, pH shift and precursor feeding strategy for fermentation process by the mutant of Streptomyces sp. FR-008 in a stirred tank bioreactor was developed. According to the process parameters analysis, the effectiveness of the strategy was examined and confirmed by experiments. A maximal CS103 concentration of 139.98 μg/mL was obtained, 2.05-fold higher than that in the pHuncontrolled fermentation. Compared to other three cases as pH-uncontrolled, pHcontrolled, and two-stage pH-controlled batch cultures, the proposed "pH shift and precursor feeding strategy" effectively avoided the scarcity of the antibiotic precursor, increased the CS103 yield from biomass (Y P/X ) and substrate (Y P/S ) by 110.61% and 48.52%, respectively, and at the time the fermentation time was shortened from 120 to 96 h. The highest CS103 production rate (1.46 μg mL −1 h −1 ) of the pH shift and precursor feeding strategy was 284.21%, 97.30%, and 58.70% higher than that of pH-uncontrolled, pH-controlled, and two-stage pH-controlled batch culture cases, respectively.

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Quantitative structure-activity relationships in amphotericin B derivatives

Cited by 131 publications

References 13 publications

Influence of a lipid bilayer on the conformational behavior of amphotericin B derivatives — A molecular dynamics study

Influence of a lipid bilayer on the conformational behavior of amphotericin B derivatives — A molecular dynamics study

Molecular modeling of amphotericin B–ergosterol primary complex in water II

The pH Shift and Precursor Feeding Strategy in a Low-Toxicity FR-008/Candicidin Derivative CS103 Fermentation Bioprocess by a Mutant of Streptomyces sp. FR-008

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