The role of the carboxyl and amino groups of polyene macrolides in their interactions with sterols and their selective toxicity. A 31P-NMR study

Hervé, Martine; Debouzy, Jean‐Claude; Borowski, Edward; Cybulska, Barbara; Gary-Bobo, C.M.

doi:10.1016/0005-2736(89)90312-x

Cited by 96 publications

(61 citation statements)

References 26 publications

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“…It was previously shown that the presence of an ionizable amino group within the polar head of the AmB derivatives is essential for channel-forming activity to occur in chemotherapeutically relevant concentrations [52]. Therefore the current study as well as our earlier simulations [21,26] suggest that the mechanism of polyene-induced permeabilization may require a specific and stable interaction between the antibiotic polar head and the phospholipid headgroups.…”

supporting

confidence: 58%

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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supporting

confidence: 58%

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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“…• the number and position of the double bonds in the sterols' ring system do not essentially influence the AmB-sterol interactions [10].…”

Section: Discussionmentioning

confidence: 98%

“…The antibiotic preferentially binds to the membranes that contain a sterol with the double bond in this moiety [10]. This structural factor seems to constitute the major and, moreover, the only so far identified molecular feature of sterols which correlates with the differential affinity of AmB to its membrane sterol targets.…”

Section: Accepted M Manuscriptmentioning

confidence: 99%

“…All these models presuppose that van der Waals interactions of the AmB chromophore and the lipophilic part of sterols preserve such complexes, although coulombic forces may also play a significant role in the proper placement of complex constituents. In the earliest proposal put forward by Herve et al the sterol hydroxyl group is bound to the charged fragments of the antibiotic molecule [10]. Mazerski and coworkers [8] postulate that the primary complex could be a part or the complete structure of the deKruijff's channel [5].…”

Section: Introductionmentioning

confidence: 99%

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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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“…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]. This system of bonds is equally strong in polyenecholesterol and polyene-ergosterol complexes.…”

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.

show abstract

The role of the carboxyl and amino groups of polyene macrolides in their interactions with sterols and their selective toxicity. A 31P-NMR study

Cited by 96 publications

References 26 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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