Novel Bacterial Topoisomerase Inhibitors: Challenges and Perspectives in Reducing hERG Toxicity

Kolarič, Anja; Minovski, Nikola

doi:10.4155/fmc-2018-0272

Cited by 23 publications

(32 citation statements)

References 19 publications

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“…Due to the spaciousness of NBTI’s binding pocket, particularly at its entrance surrounding the NBTI’s linker moiety, the linker itself makes only one critical contact with the enzyme, and not with the DNA; nevertheless, it has still an important role in the NBTIs activity. 57 The linker is responsible for the appropriate spatial orientation of both the LHS and RHS fragments, and more importantly, it influences the physicochemical and pharmacological properties of NBTIs that are crucial for their suitable antibacterial activity and safety profile, and in particular, in their hERG inhibitory activity. The linker usually consists of three parts: an ethyl moiety connected to the LHS fragment, a cyclic moiety, and a secondary amine connected to the RHS fragment ( Figures 1 and 4 ).…”

Section: The Linkermentioning

confidence: 99%

The Structural Features of Novel Bacterial Topoisomerase Inhibitors That Define Their Activity on Topoisomerase IV

et al. 2022

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The continued emergence of bacterial resistance has created an urgent need for new and effective antibacterial agents. Bacterial type II topoisomerases, such as DNA gyrase and topoisomerase IV (topoIV), are well-validated targets for antibacterial chemotherapy. The novel bacterial topoisomerase inhibitors (NBTIs) represent one of the new promising classes of antibacterial agents. They can inhibit both of these bacterial targets; however, their potencies differ on the targets among species, making topoIV probably a primary target of NBTIs in Gram-negative bacteria. Therefore, it is important to gain an insight into the NBTIs key structural features that govern the topoIV inhibition. However, in Gram-positive bacteria, topoIV is also a significant target for achieving dual-targeting, which in turn contributes to avoiding bacterial resistance caused by single-target mutations. In this perspective, we address the structure–activity relationship guidelines for NBTIs that target the topoIV enzyme in Gram-positive and Gram-negative bacteria.

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Section: The Linkermentioning

confidence: 99%

The Structural Features of Novel Bacterial Topoisomerase Inhibitors That Define Their Activity on Topoisomerase IV

et al. 2022

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“…1 for chemical structures). Although many potent NBTIs with good antibacterial activity have been reported, a major challenge remains hERG toxicity [42], [46], for which target-bound structure are not particularly helpful.…”

Section: The Role Of S Aureus Gyrasecore Crystallization System In Cmentioning

confidence: 99%

DNA Topoisomerase Inhibitors: Trapping a DNA-Cleaving Machine in Motion

Bax

Murshudov

Maxwell

et al. 2019

Journal of Molecular Biology

131

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Type II topoisomerases regulate DNA topology by making a double-stranded break in one DNA duplex, transporting another DNA segment through this break and then resealing it. Bacterial type IIA topoisomerase inhibitors, such as fluoroquinolones and novel bacterial topoisomerase inhibitors, can trap DNA cleavage complexes with double- or single-stranded cleaved DNA. To study the mode of action of such compounds, 21 crystal structures of a “gyrase CORE ” fusion truncate of Staphyloccocus aureus DNA gyrase complexed with DNA and diverse inhibitors have been published, as well as 4 structures lacking inhibitors. These structures have the DNA in various cleavage states and appear to track trajectories along the catalytic paths of the DNA cleavage/religation steps. The various conformations sampled by these multiple “gyrase CORE ” structures show rigid body movements of the catalytic GyrA WHD and GyrB TOPRIM domains across the dimer interface. Conformational changes common to all compound-bound structures suggest common mechanisms for DNA cleavage-stabilizing compounds. The structures suggest that S. aureus gyrase uses a single moving-metal ion for cleavage and that the central four base pairs need to be stretched between the two catalytic sites, in order for a scissile phosphate to attract a metal ion to the A-site to catalyze cleavage, after which it is “stored” in another coordination configuration (B-site) in the vicinity. We present a simplified model for the catalytic cycle in which capture of the transported DNA segment causes conformational changes in the ATPase domain that push the DNA gate open, resulting in stretching and cleaving the gate-DNA in two steps.

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“…Of note, an important NBTI class-related effect is a tendency to inhibit hERG potassium channels. 38 Accordingly, to further assess the toxicity profiles of these compounds, it is necessary to evaluate their hERG cardiotoxic potential, which we plan to do in the future.…”

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confidence: 99%

Structurally Optimized Potent Dual-Targeting NBTI Antibacterials with an Enhanced Bifurcated Halogen-Bonding Propensity

Kokot

Weiss

Zdovc

et al. 2021

ACS Med. Chem. Lett.

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We designed and synthesized an optimized library of novel bacterial topoisomerase inhibitors with p -halogenated phenyl right-hand side fragments and significantly enhanced and balanced dual-targeted DNA gyrase and topoisomerase IV activities of Staphylococcus aureus and Escherichia coli . By increasing the electron-withdrawing properties of the p -halogenated phenyl right-hand side fragment and maintaining a similar lipophilicity and size, an increased potency was achieved, indicating that the antibacterial activities of this series of novel bacterial topoisomerase inhibitors against all target enzymes are determined by halogen-bonding rather than van der Waals interactions. They show nanomolar enzyme inhibitory and whole-cell antibacterial activities against S. aureus and methicillin-resistant S. aureus (MRSA) strains. However, due to the relatively high substrate specificity for the bacterial efflux pumps, they tend to be less potent against E. coli and other Gram-negative pathogens.

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Novel Bacterial Topoisomerase Inhibitors: Challenges and Perspectives in Reducing hERG Toxicity

Cited by 23 publications

References 19 publications

The Structural Features of Novel Bacterial Topoisomerase Inhibitors That Define Their Activity on Topoisomerase IV

The Structural Features of Novel Bacterial Topoisomerase Inhibitors That Define Their Activity on Topoisomerase IV

DNA Topoisomerase Inhibitors: Trapping a DNA-Cleaving Machine in Motion

Structurally Optimized Potent Dual-Targeting NBTI Antibacterials with an Enhanced Bifurcated Halogen-Bonding Propensity

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