DNA as a target for antimicrobials

Bolhuis, Albert; Aldrich‐Wright, Janice R.

doi:10.1016/j.bioorg.2014.03.009

Cited by 37 publications

(16 citation statements)

References 80 publications

(80 reference statements)

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“…The cellular uptake efficiency for synthetic DNA intercalators is essential for therapeutic and imaging applications in vivo ( 31 , 38 ). Although the monomer Δ-P was demonstrated recently to exhibit in vivo antibiotic activity in treating bacterial infection of soil nematode ( 109 ), the binuclear ruthenium complexes Δ,Δ-P and Δ,Δ-Pc had less definite cellular uptake in vitro ( 38 ). In the absence of an effective drug delivery scheme, the high DNA binding affinity of these unconventional intercalators is insufficient to qualify them as DNA-targeting drug candidates.…”

Section: Optimizing Dna Intercalation Propertiesmentioning

confidence: 99%

“…The urgent quest for synthesizing new therapeutic small molecules and optimizing currently used agents is fueled by a fierce race to surpass the molecular evolution of drug resistance. Studies showed that combining drugs that have different binding modes to DNA, such as intercalation and cross linking, lowers the chance of cancer reoccurrence ( 19 , 109 ). Aside from the important applications of DNA intercalators, these small molecules serve as basic models that may improve our capacity to examine and understand much bigger and more complicated biological systems.…”

Section: Optimizing Dna Intercalation Propertiesmentioning

confidence: 99%

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Mechanisms of small molecule–DNA interactions probed by single-molecule force spectroscopy

et al. 2016

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There is a wide range of applications for non-covalent DNA binding ligands, and optimization of such interactions requires detailed understanding of the binding mechanisms. One important class of these ligands is that of intercalators, which bind DNA by inserting aromatic moieties between adjacent DNA base pairs. Characterizing the dynamic and equilibrium aspects of DNA-intercalator complex assembly may allow optimization of DNA binding for specific functions. Single-molecule force spectroscopy studies have recently revealed new details about the molecular mechanisms governing DNA intercalation. These studies can provide the binding kinetics and affinity as well as determining the magnitude of the double helix structural deformations during the dynamic assembly of DNA–ligand complexes. These results may in turn guide the rational design of intercalators synthesized for DNA-targeted drugs, optical probes, or integrated biological self-assembly processes. Herein, we survey the progress in experimental methods as well as the corresponding analysis framework for understanding single molecule DNA binding mechanisms. We discuss briefly minor and major groove binding ligands, and then focus on intercalators, which have been probed extensively with these methods. Conventional mono-intercalators and bis-intercalators are discussed, followed by unconventional DNA intercalation. We then consider the prospects for using these methods in optimizing conventional and unconventional DNA-intercalating small molecules.

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Section: Optimizing Dna Intercalation Propertiesmentioning

confidence: 99%

Section: Optimizing Dna Intercalation Propertiesmentioning

confidence: 99%

Mechanisms of small molecule–DNA interactions probed by single-molecule force spectroscopy

et al. 2016

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“…The association of DNA-targeting drugs with nucleic acids [1][2][3][4][5][6][7][8] is considered one of the essential properties that determine their biological activity [9]. Specifically, a ligand may occupy particular binding sites of DNA or induce significant structural changes of the nucleic acid.…”

Section: Introductionmentioning

confidence: 99%

“…In turn, both of these pro-cesses interfere with biologically relevant recognition processes between DNA and enzymes, e.g., topoisomerase [10]. Therefore, many potential lead structures of chemotherapeutic anticancer drugs exhibit DNA-binding properties [1][2][3][4][5][6][7][8][9][10]. Nevertheless, most DNA-binding ligands have an insufficient selec- tivity towards the targeted nucleic acid, and they also accumulate in healthy tissue, so that the chemotherapeutic treatment of tumors with DNA-binding drugs still suffers from severe side effects because of the intrinsic toxicity of the employed drugs [11][12][13].…”

Section: Introductionmentioning

confidence: 99%

Reversible photoswitching of the DNA-binding properties of styrylquinolizinium derivatives through photochromic [2 + 2] cycloaddition and cycloreversion

Kölsch¹,

Ihmels²,

Mattay³

et al. 2020

Beilstein J. Org. Chem.

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It was demonstrated that styrylquinolizinium derivatives may be applied as photoswitchable DNA ligands. At lower ligand:DNA ratios (≤1.5), these compounds bind to duplex DNA by intercalation, with binding constants ranging from K b = 4.1 × 104 M to 2.6 × 105 M (four examples), as shown by photometric and fluorimetric titrations as well as by CD and LD spectroscopic analyses. Upon irradiation at 450 nm, the methoxy-substituted styrylquinolizinium derivatives form the corresponding syn head-to-tail cyclobutanes in a selective [2 + 2] photocycloaddition, as revealed by X-ray diffraction analysis of the reaction products. These photodimers bind to DNA only weakly by outside-edge association, but they release the intercalating monomers upon irradiation at 315 nm in the presence of DNA. As a result, it is possible to switch between these two ligands and likewise between two different binding modes by irradiation with different excitation wavelengths.

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“…As recently reviewed by us, these complexes interact with DNA through intercalation [14]. It is important to note that complex formation is important, as the biological activity is significantly enhanced when compared to ligands or metals alone [15,16].…”

Section: Introductionmentioning

confidence: 99%

The antimicrobial and antibiofilm activities of copper(II) complexes

Beeton

Aldrich‐Wright

Bolhuis

2014

Journal of Inorganic Biochemistry

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Gram-positive and Gram-negative bacteria, albeit that activity was generally higher for the former. The antibiofilm activity was then determined against a clinical isolate of meticillin-resistant Staphylococcus aureus (MRSA). Strikingly, the copper complexes tested showed significant activity against biofilms, and were better in the removal of biofilms than vancomycin, an antibiotic that is currently used in the treatment of MRSA infections.

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DNA as a target for antimicrobials

Cited by 37 publications

References 80 publications

Mechanisms of small molecule–DNA interactions probed by single-molecule force spectroscopy

Mechanisms of small molecule–DNA interactions probed by single-molecule force spectroscopy

Reversible photoswitching of the DNA-binding properties of styrylquinolizinium derivatives through photochromic [2 + 2] cycloaddition and cycloreversion

The antimicrobial and antibiofilm activities of copper(II) complexes

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