Vancomycin and related antibiotics

Perkins, H. R.

doi:10.1016/0163-7258(82)90053-5

Cited by 82 publications

(70 citation statements)

References 65 publications

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“…Interestingly, our results support the conclusion that sterol binding is also primarily responsible for the antifungal action of natamycin (21), and several antibacterial peptides exert their effects via specific lipid binding as well (44)(45)(46)(47). Collectively, these findings suggest that the potential generality of this mode of action is substantial.…”

Section: Discussionsupporting

confidence: 76%

Amphotericin primarily kills yeast by simply binding ergosterol

Gray

Palacios

Dailey

et al. 2012

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

475

408

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Amphotericin B (AmB) is a prototypical small molecule natural product that can form ion channels in living eukaryotic cells and has remained refractory to microbial resistance despite extensive clinical utilization in the treatment of life-threatening fungal infections for more than half a century. It is now widely accepted that AmB kills yeast primarily via channel-mediated membrane permeabilization. Enabled by the iterative cross-coupling-based synthesis of a functional group deficient derivative of this natural product, we have discovered that channel formation is not required for potent fungicidal activity. Alternatively, AmB primarily kills yeast by simply binding ergosterol, a lipid that is vital for many aspects of yeast cell physiology. Membrane permeabilization via channel formation represents a second complementary mechanism that further increases drug potency and the rate of yeast killing. Collectively, these findings (i) reveal that the binding of a physiologically important microbial lipid is a powerful and clinically validated antimicrobial strategy that may be inherently refractory to resistance, (ii) illuminate a more straightforward path to an improved therapeutic index for this clinically vital but also highly toxic antifungal agent, and (iii) suggest that the capacity for AmB to form proteinlike ion channels might be separable from its cytocidal effects.small molecules | protein-like functions | N-methyliminodiacetic acid boronates

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Section: Discussionsupporting

confidence: 76%

Amphotericin primarily kills yeast by simply binding ergosterol

Gray

Palacios

Dailey

et al. 2012

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

475

408

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“…The primary biological target for vancomycin and the glycopeptide antibiotics is bacterial cell wall precursors containing D-Ala-D-Ala, binding to which results in inhibition of cell wall maturation (29). This target is unique to bacteria and contributes to the selectivity of the antibiotic class for bacteria vs. their mammalian hosts.…”

Section: Significancementioning

confidence: 99%

Peripheral modifications of [Ψ[CH ₂ NH]Tpg ⁴ ]vancomycin with added synergistic mechanisms of action provide durable and potent antibiotics

Okano

Isley

Boger

2017

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

171

215

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Significance In a quest for antibiotics that may display durable clinical lifetimes, analogs of the glycopeptide antibiotics, including vancomycin, have been designed that not only directly overcome the molecular basis of existing vancomycin resistance but also contain two added peripheral modifications that endow them with two additional independent mechanisms of actions not found in the parent antibiotics. It is shown that such peripherally and binding pocket-modified vancomycin analogs display little propensity for acquired resistance by vancomycin-resistant Enterococci and that both their antimicrobial potency and durability against such challenges follow trends (three > two > one mechanisms of action) that are now predictable.

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“…Inhibition of bacterial cell-wall growth by vancomycin is based on noncovalent binding of the antibiotic to cell-wall precursors containing the C-terminal sequence KAA (LDD) [15][16][17]. The solution-phase structures of complexes formed between the vancomycin-group antibiotics and several small bacterial cell-wall mimicking peptides have been elucidated using NMR spectroscopy [3, 18 -20] and X-Ray [6, 21,22].…”

Section: Vancomycin-peptide Noncovalent Complexesmentioning

confidence: 99%

Fluorescence lifetime probe of biomolecular conformations

Shi¹,

Parks²

2010

J. Am. Soc. Mass Spectrom.

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Methods have been developed to measure the fluorescence lifetime versus temperature of trapped biomolecular ions derivatized with a fluorescent dye. Previous measurements for different sequences of polyproline peptides demonstrated that quenching rates are related to conformations and their spatial fluctuations. This paper presents the results of extending these methods to study the conformational dynamics of larger biomolecules. Vancomycin-peptide noncovalent complexes in the 1ϩ charge state were studied as a function of temperature for different W-KAA peptide chiralities (L-LDD, D-LDD, L-DLL). Fluorescence-quenching rates, k q , were found to be stereoselective for these different chiralities with relative magnitudesThe variation in fluorescent quenching resulting from switching the chirality of the single Trp residue was readily detectable. Molecular dynamics analysis of complexes formed by W-KAA (L-LDD) and W-KAA(L-DLL) indicates that increased flexibility in the (L-DLL) complex is correlated with reduced quenching rates. Fluorescence measurements were also performed for the Trp-cage protein comparing quenching rates in the 1ϩ, 2ϩ, and 3ϩ charge states for which k q. Measurements of a sequence including a single-point mutation infer the presence of a salt-bridge structure in the 1ϩ charge state and its absence in both the 2ϩ and 3ϩ states. Molecular dynamics structures of Trp-cage indicate that a salt bridge in the 1ϩ charge state produces more compact conformations leading to larger quenching rates based on the quenching mechanism. In both these experimental studies the fluorescence-quenching rates were consistent with changes in structure induced by either intermolecular or intramolecular interactions. (J Am Soc Mass Spectrom 2010, 21, 707-718) © 2010 American Society for Mass Spectrometry P revious measurements [1] of the lifetime of a fluorescent dye covalently bound to polypeptide ions exhibited a quenching rate that depends both on the separation of the dye to a Trp side chain and on the strength of electrostatic fields in the vicinity of the dye. Quenching rates were found to depend on specific peptide sequences giving rise to different conformations and spatial fluctuations characterized by each conformation. Consequently, lifetime measurements provide an opportunity to extract information sensitive to local molecular arrangements and, perhaps more importantly, changes in that arrangement determined by intramolecular and intermolecular interactions. This paper applies lifetime measurements to study two larger biomolecules: the vancomycin-peptide noncovalent complex and the Trp-cage protein. The structures of these biomolecules have been identified in NMR solution measurements; and each has been studied previously in gas-phase measurements. Results of gas-phase studies of the vancomycin-peptide complex infer that specific changes in the peptide ligand chirality lead to different hydrogen binding networks and thus to different conformations. Gas-phase measurements and calculations of Trp-cage protein i...

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Vancomycin and related antibiotics

Cited by 82 publications

References 65 publications

Amphotericin primarily kills yeast by simply binding ergosterol

Amphotericin primarily kills yeast by simply binding ergosterol

Peripheral modifications of [Ψ[CH ₂ NH]Tpg ⁴ ]vancomycin with added synergistic mechanisms of action provide durable and potent antibiotics

Fluorescence lifetime probe of biomolecular conformations

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Vancomycin and related antibiotics

Cited by 82 publications

References 65 publications

Amphotericin primarily kills yeast by simply binding ergosterol

Amphotericin primarily kills yeast by simply binding ergosterol

Peripheral modifications of [Ψ[CH 2 NH]Tpg 4 ]vancomycin with added synergistic mechanisms of action provide durable and potent antibiotics

Fluorescence lifetime probe of biomolecular conformations

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Peripheral modifications of [Ψ[CH ₂ NH]Tpg ⁴ ]vancomycin with added synergistic mechanisms of action provide durable and potent antibiotics