Abstract
The modulation of DNA topology by DNA gyrase and topoisomerase IV, both of which are type IIA topoisomerases and found in most bacteria, is a function vital to DNA replication, repair and decatenation. Despite the potential for resistance development, DNA gyrase and/or topoisomerase IV have been proven to be and remain highly attractive targets in antibacterial drug discovery due to their potential for dual targeting. The search for new GyrA and/or ParC inhibitors that can overcome the increasing spread of multidrug-resistant bacteria has been successfully focused in the last decades on the modification of the known fluoroquinolone scaffold as primarily guided by ligand-based design via classical structure-activity relationship studies and the optimisation of physicochemical properties. This focus has resulted in several novel fluoroquinolones that have been introduced into clinical practice since 2000, and several of these new compounds are currently in different phases of clinical trials. Due to increasing resistance to fluoroquinolones, a significant part of DNA gyrase research has shifted to the discovery of new GyrB and/or ParE inhibitors, which are commonly identified through fragment-based design as well as virtual screening techniques and structure-based hit optimisation programs. This research often results in lead compounds with potent inhibitory activity and promising antibacterial activity profiles. Nevertheless, it is important to understand how different physicochemical properties (e.g., logD and total polar surface area) and different structural motifs influence the compounds’ permeability to ensure the efficient discovery of potent, small-molecule antibacterials particularly against Gram-negative strains.
Keywords: Antibacterial, ATP, DNA gyrase, dual inhibitors, structure-based design, topoisomerase.
Current Topics in Medicinal Chemistry
Title:Prospects for Developing New Antibacterials Targeting Bacterial Type IIA Topoisomerases
Volume: 14 Issue: 1
Author(s): Tihomir Tomašić and Lucija Peterlin Mašič
Affiliation:
Keywords: Antibacterial, ATP, DNA gyrase, dual inhibitors, structure-based design, topoisomerase.
Abstract: The modulation of DNA topology by DNA gyrase and topoisomerase IV, both of which are type IIA topoisomerases and found in most bacteria, is a function vital to DNA replication, repair and decatenation. Despite the potential for resistance development, DNA gyrase and/or topoisomerase IV have been proven to be and remain highly attractive targets in antibacterial drug discovery due to their potential for dual targeting. The search for new GyrA and/or ParC inhibitors that can overcome the increasing spread of multidrug-resistant bacteria has been successfully focused in the last decades on the modification of the known fluoroquinolone scaffold as primarily guided by ligand-based design via classical structure-activity relationship studies and the optimisation of physicochemical properties. This focus has resulted in several novel fluoroquinolones that have been introduced into clinical practice since 2000, and several of these new compounds are currently in different phases of clinical trials. Due to increasing resistance to fluoroquinolones, a significant part of DNA gyrase research has shifted to the discovery of new GyrB and/or ParE inhibitors, which are commonly identified through fragment-based design as well as virtual screening techniques and structure-based hit optimisation programs. This research often results in lead compounds with potent inhibitory activity and promising antibacterial activity profiles. Nevertheless, it is important to understand how different physicochemical properties (e.g., logD and total polar surface area) and different structural motifs influence the compounds’ permeability to ensure the efficient discovery of potent, small-molecule antibacterials particularly against Gram-negative strains.
Export Options
About this article
Cite this article as:
Tomašić Tihomir and Mašič Peterlin Lucija, Prospects for Developing New Antibacterials Targeting Bacterial Type IIA Topoisomerases, Current Topics in Medicinal Chemistry 2014; 14 (1) . https://dx.doi.org/10.2174/1568026613666131113153251
DOI https://dx.doi.org/10.2174/1568026613666131113153251 |
Print ISSN 1568-0266 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4294 |
Call for Papers in Thematic Issues
Chemistry Based on Natural Products for Therapeutic Purposes
The development of new pharmaceuticals for a wide range of medical conditions has long relied on the identification of promising natural products (NPs). There are over sixty percent of cancer, infectious illness, and CNS disease medications that include an NP pharmacophore, according to the Food and Drug Administration. Since NP ...read more
Current Trends in Drug Discovery Based on Artificial Intelligence and Computer-Aided Drug Design
Drug development discovery has faced several challenges over the years. In fact, the evolution of classical approaches to modern methods using computational methods, or Computer-Aided Drug Design (CADD), has shown promising and essential results in any drug discovery campaign. Among these methods, molecular docking is one of the most notable ...read more
Drug Discovery in the Age of Artificial Intelligence
In the age of artificial intelligence (AI), we have witnessed a significant boom in AI techniques for drug discovery. AI techniques are increasingly integrated and accelerating the drug discovery process. These developments have not only attracted the attention of academia and industry but also raised important questions regarding the selection ...read more
From Biodiversity to Chemical Diversity: Focus of Flavonoids
Flavonoids are the largest group of polyphenols, plant secondary metabolites arising from the essential aromatic amino acid phenylalanine (or more rarely from tyrosine) via the phenylpropanoid pathway. The flavan nucleus is the basic 15-carbon skeleton of flavonoids (C6-C3-C6), which consists of two phenyl rings (A and B) and a heterocyclic ...read more
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
- Announcements
Related Articles
-
Antidiabetic Agents in Patients with Chronic Kidney Disease and End-Stage Renal Disease on Dialysis: Metabolism and Clinical Practice
Current Drug Metabolism Tropism-Modified Adenoviral and Adeno-Associated Viral Vectors for Gene Therapy
Current Gene Therapy Investigating Drug-induced Mitochondrial Toxicity: A Biosensor to Increase Drug Safety?
Current Drug Safety Cardioprotective Effects of Natural Products <i>via</i> the Nrf2 Signaling Pathway
Current Vascular Pharmacology Targeting Protein Kinases in the Malaria Parasite: Update of an Antimalarial Drug Target
Current Topics in Medicinal Chemistry Invasive aspergillosis: adjunctive combination therapy
Mini-Reviews in Medicinal Chemistry Circulating MicroRNAs as Biomarkers for Inflammatory Diseases
MicroRNA The Role of Fibrate Treatment in Dyslipidemia: An Overview
Current Pharmaceutical Design Antioxidant Therapy in Critically Septic Patients
Current Drug Targets PDE-5 Inhibitors for BPH-Associated LUTS
Current Drug Targets Omentin: Linking Metabolic Syndrome and Cardiovascular Disease
Current Vascular Pharmacology Simultaneous Determination of Simvastatin with Caffeine in Bulk Drug, Formulation and their Monitoring in Mice Plasma Through HPLC-PDA Technique
Current Analytical Chemistry Modulating Agents in Resistant Malaria
Drug Design Reviews - Online (Discontinued) Biogenic Peptides and Their Potential Use
Current Pharmaceutical Design Synthetic Hammerhead Ribozymes as Therapeutic Tools to Control Disease Genes
Current Gene Therapy Artificial Blood: A Futuristic Dimension of Modern Day Transfusion Sciences
Cardiovascular & Hematological Agents in Medicinal Chemistry Cyclodextrin Based Nanosponges: A Multidimensional Drug Delivery System and its Biomedical Applications
Current Drug Delivery A Comprehensive Review on the Biological and Pharmacological Activities of Rhodanine Based Compounds for Research and Development of Drugs
Mini-Reviews in Medicinal Chemistry Depression and Disturbed Bone Metabolism: A Narrative Review of the Epidemiological Findings and Postulated Mechanisms
Current Molecular Medicine Intraarticular Treatments for Osteoarthritis: New Perspectives
Current Drug Targets