Structural Aspects of DNA Gyrase Targeted by Novel Bacterial Topoisomerase Inhibitors.

In this Letter, we present a small series of novel bacterial topoisomerase inhibitors (NTBIs) that exhibit both potent inhibition of DNA gyrase and potent antimycobacterial activity. The disclosed crystal structure of DNA gyrase in complex with DNA and compound from this NBTI series reveals the binding mode of an NBTI in the GyrA binding pocket and confirms the presence and importance of halogen bonding for the excellent on-target potency. In addition, we have shown that compound is a promising DNA gyrase inhibitor, with an IC for gyrase of 0.

Enhancing Antibacterial Efficacy: Combining Novel Bacterial Topoisomerase Inhibitors with Efflux Pump Inhibitors and Other Agents Against Gram-Negative Bacteria.

Background: The novel bacterial topoisomerase inhibitors (NBTIs) developed in our laboratory show potent on-target enzyme inhibition but suffer from low activity against Gram-negative bacteria.

Methods: With the aim of improving the antibacterial activity of our compounds against Gram-negative bacteria, we tested them in combination with different efflux pump inhibitors (EPIs), a strategy that showed promise in several other classes of antimicrobials. We also investigated the combined effect of NBTIs with ATP-competitive inhibitors of bacterial type II topoisomerases (ACIs), as well as the antibiofilm properties of our compounds and the combination with EPIs against early and mature biofilm.

Dynamic Profiling and Binding Affinity Prediction of NBTI Antibacterials against DNA Gyrase Enzyme by Multidimensional Machine Learning and Molecular Dynamics Simulations.

Bacterial type II topoisomerases are well-characterized and clinically important targets for antibacterial chemotherapy. Novel bacterial topoisomerase inhibitors (NBTIs) are a newly disclosed class of antibacterials. Prediction of their binding affinity to these enzymes would be beneficial for design/optimization of new NBTIs.

The overview of development of novel bacterial topoisomerase inhibitors effective against multidrug-resistant bacteria in an academic environment: From early hits to in vivo active antibacterials.

Antimicrobial resistance caused by the excessive and inappropriate use of antibacterial drugs is a global health concern. Currently, we are walking a fine line between the fact that most bacterial infections can still be cured with the antibiotics known so far, and the emergence of infections with bacteria resistant to several drugs at the same time, against which we no longer have an effective drug. Therefore, new antibacterial drugs are urgently needed to curb the hard-to-treat infections.

Exploring Alternative Pathways to Target Bacterial Type II Topoisomerases Using NBTI Antibacterials: Beyond Halogen-Bonding Interactions.

Novel bacterial topoisomerase inhibitors (NBTIs) are a new class of antibacterial agents that target bacterial type II topoisomerases (DNA gyrase and topoisomerase IV). Our recently disclosed crystal structure of an NBTI ligand in complex with DNA gyrase and DNA revealed that the halogen atom in the para position of the phenyl right hand side (RHS) moiety is able to establish strong symmetrical bifurcated halogen bonds with the enzyme; these are responsible for the excellent enzyme inhibitory potency and antibacterial activity of these NBTIs. To further assess the possibility of any alternative interactions (e.

Amide containing NBTI antibacterials with reduced hERG inhibition, retained antimicrobial activity against gram-positive bacteria and in vivo efficacy.

Novel bacterial topoisomerase inhibitors (NBTIs) are new promising antimicrobials for the treatment of multidrug-resistant bacterial infections. In recent years, many new NBTIs have been discovered, however most of them struggle with the same issue - the balance between antibacterial activity and hERG-related toxicity. We started a new campaign by optimizing the previous series of NBTIs, followed by the design and synthesis of a new, amide-containing focused NBTI library to reduce hERG inhibition and maintain antibacterial activity against Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA).

Diminishing hERG inhibitory activity of aminopiperidine-naphthyridine linked NBTI antibacterials by structural and physicochemical optimizations.

Novel bacterial topoisomerase inhibitors (NBTIs) are an important new class of antibacterials targeting bacterial type II topoisomerases (DNA gyrase and topoisomerase IV). Notwithstanding their potent antibacterial activity, they suffer from a detrimental class-related hERG blockage. In this study, we designed and synthesized an optimized library of NBTIs comprising different linker moieties that exhibit reduced hERG inhibition and retain inhibitory potencies on DNA gyrase and topoisomerase IV of Staphylococcus aureus and Escherichia coli, respectively, as well as potent antibacterial activities.

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

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.

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

We designed and synthesized an optimized library of novel bacterial topoisomerase inhibitors with -halogenated phenyl right-hand side fragments and significantly enhanced and balanced dual-targeted DNA gyrase and topoisomerase IV activities of and . By increasing the electron-withdrawing properties of the -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 and methicillin-resistant (MRSA) strains.

A Fine-Tuned Lipophilicity/Hydrophilicity Ratio Governs Antibacterial Potency and Selectivity of Bifurcated Halogen Bond-Forming NBTIs.

Herein, we report the design of a focused library of novel bacterial topoisomerase inhibitors (NBTIs) based on innovative mainly monocyclic right-hand side fragments active against DNA gyrase and Topo IV. They exhibit a very potent and wide range of antibacterial activity, even against some of the most concerning hard-to-treat pathogens for which new antibacterials are urgently needed, as reported by the WHO and CDC. NBTIs enzyme activity and whole cell potency seems to depend on the fine-tuned lipophilicity/hydrophilicity ratio that governs the permeability of those compounds through the bacterial membranes.