scholarly journals Delafloxacin, Finafloxacin, and Zabofloxacin: Novel Fluoroquinolones in the Antibiotic Pipeline

Antibiotics ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 1506
Author(s):  
Béla Kocsis ◽  
Dániel Gulyás ◽  
Dóra Szabó
Keyword(s):  
Broad Spectrum ◽  
Bacterial Infections ◽  
Chemical Structure ◽  
Antimicrobial Agents ◽  
Treatment Options ◽  
Dna Gyrase ◽  
Daily Practice ◽  
Molecular Surface ◽  
Chronic Obstructive ◽  
Topoisomerase Iv

Novel antimicrobial agents, approved for clinical use in past years, represent potential treatment options for various infections. In this review, we summarize the most important medical and microbiological features of three recently approved fluoroquinolones, namely delafloxacin, finafloxacin, and zabofloxacin. Delafloxacin possesses an anionic chemical structure, and represents broad-spectrum activity, as it targets both bacterial DNA gyrase and topoisomerase IV enzymes of gram-positive and gram-negative bacteria with equal affinity. Its molecular surface is larger than that of other fluoroquinolones, and it has enhanced antibacterial efficacy in acidic environments. Delafloxacin has been approved to treat acute bacterial skin and skin-structure infections, as well as community-acquired bacterial pneumonia. Finafloxacin has a zwitterionic chemical structure, and targets both DNA gyrase and topoisomerase IV enzymes. This enables a broad antibacterial spectrum; however, finafloxacin has so far only been approved in ear-drops to treat bacterial otitis externa. Zabofloxacin is also a broad-spectrum fluoroquinolone agent, and was first approved in South Korea to treat acute bacterial exacerbation of chronic obstructive pulmonary disease. The introduction of these novel fluoroquinolones into daily practice extends the possible indications of antibiotics into different bacterial infections, and provides treatment options in difficult-to-treat infections. However, some reports of delafloxacin resistance have already appeared, thus underlining the importance of the prudent use of antibiotics.

scholarly journals Design, Synthesis and Antimicrobial Evaluation of New Norfloxacin-Naphthoquinone Hybrid Molecules

Proceedings ◽  
2019 ◽  
Vol 41 (1) ◽  
pp. 9 ◽  
Author(s):  
Andrea Defant ◽  
Alessandro Vozza ◽  
Ines Mancini
Keyword(s):  
Bacterial Infections ◽  
Antimicrobial Agents ◽  
Biological Activities ◽  
Dna Gyrase ◽  
Structural Features ◽  
Therapeutic Agents ◽  
Topoisomerase Iv ◽  
Design Synthesis ◽  
Biological Targets ◽  
Hybrid Molecules

Although the wide arsenal of drugs available to treat bacterial infections, emerging drug-resistant bacterial pathogens have recently highlighted an urgent need to find new more effective and less toxic therapeutic agents. Fluoroquinolones, including norfloxacin, are antibiotics showing a concentration-dependent bactericidal capacity due to the activity inhibition of DNA-gyrase and topoisomerase IV, which are enzymes essential for bacterial DNA replication. Naphthoquinones are secondary metabolites showing different biological activities, including cytotoxic, antibacterial and antifungal effects. In particular, the efficacy of natural and synthetic 1,4-naphthoquinone derivatives is likely due to their oxidizing/reducing capability, through which they destroy cellular targets as nucleic acids. Hybrid molecules are produced combining structural features of two or more bioactive compounds, in order to obtain new therapeutic agents able, not only to reduce undesirable side effects of the parent drugs, but also to inhibit more biological targets, hopefully with a better therapeutic property than the administration of combined single-target drugs. With the aim to apply this strategy in the study of new potential antimicrobial agents, we have synthesized four hybrid molecules by the reaction of norfloxacin with suitable quinones and their activities have been evaluated against both bacteria and fungi, in comparison with synthetic precursors. The experimental data are supported by docking calculations on S. aureus DNA-gyrase, discussing the interactions involved for each hybrid molecule, in comparison with norfloxacin and the original ligand moxifloxacin.

Synthesis of novel 2-aminobenzothiazole derivatives as potential antimicrobial agents with dual DNA gyrase/topoisomerase IV inhibition

2020 ◽  
Vol 94 ◽  
pp. 103437 ◽  
Author(s):  
Magda M.F. Ismail ◽  
Hanan Gaber Abdulwahab ◽  
Eman Samir Nossier ◽  
Nagwan Galal El Menofy ◽  
Basma Abdelhameed Abdelkhalek
Keyword(s):  
Antimicrobial Agents ◽  
Dna Gyrase ◽  
Topoisomerase Iv

scholarly journals In VitroandIn VivoCharacterization of the Novel Oxabicyclooctane-Linked Bacterial Topoisomerase Inhibitor AM-8722, a Selective, Potent Inhibitor of Bacterial DNA Gyrase

2016 ◽  
Vol 60 (8) ◽  
pp. 4830-4839 ◽  
Author(s):  
Christopher M. Tan ◽  
Charles J. Gill ◽  
Jin Wu ◽  
Nathalie Toussaint ◽  
Jingjun Yin ◽  
...  
Keyword(s):  
Broad Spectrum ◽  
Antibacterial Agents ◽  
Cell Activity ◽  
Dna Gyrase ◽  
Topoisomerase Iv ◽  
Bacterial Dna ◽  
Whole Cell ◽  
Content Type

ABSTRACTOxabicyclooctane-linked novel bacterial topoisomerase inhibitors (NBTIs) represent a new class of recently described antibacterial agents with broad-spectrum activity. NBTIs dually inhibit the clinically validated bacterial targets DNA gyrase and topoisomerase IV and have been shown to bind distinctly from known classes of antibacterial agents directed against these targets. Herein we report the molecular, cellular, andin vivocharacterization of AM-8722 as a representative N-alkylated-1,5-naphthyridone left-hand-side-substituted NBTI. Consistent with its mode of action, macromolecular labeling studies revealed a specific effect of AM-8722 to dose dependently inhibit bacterial DNA synthesis. AM-8722 displayed greater intrinsic enzymatic potency than levofloxacin versus both DNA gyrase and topoisomerase IV fromStaphylococcus aureusandEscherichia coliand displayed selectivity against human topoisomerase II. AM-8722 was rapidly bactericidal and exhibited whole-cell activity versus a range of Gram-negative and Gram-positive organisms, with no whole-cell potency shift due to the presence of DNA or human serum. Frequency-of-resistance studies demonstrated an acceptable rate of resistance emergencein vitroat concentrations 16- to 32-fold the MIC. AM-8722 displayed acceptable pharmacokinetic properties and was shown to be efficacious in mouse models of bacterial septicemia. Overall, AM-8722 is a selective and potent NBTI that displays broad-spectrum antimicrobial activityin vitroandin vivo.

scholarly journals Crumbling the Castle: Targeting DNABII Proteins for Collapsing Bacterial Biofilms as a Therapeutic Approach to Treat Disease and Combat Antimicrobial Resistance

Antibiotics ◽  
2022 ◽  
Vol 11 (1) ◽  
pp. 104
Author(s):  
James V. Rogers ◽  
Veronica L. Hall ◽  
Charles C. McOsker
Keyword(s):  
Antimicrobial Resistance ◽  
Bacterial Infections ◽  
Antimicrobial Agents ◽  
Defense Mechanism ◽  
Treatment Options ◽  
Bacterial Biofilms ◽  
Host Immune System ◽  
New Antibiotics ◽  
Financial Burdens ◽  
Global Threat

Antimicrobial resistance (AMR) is a concerning global threat that, if not addressed, could lead to increases in morbidity and mortality, coupled with societal and financial burdens. The emergence of AMR bacteria can be attributed, in part, to the decreased development of new antibiotics, increased misuse and overuse of existing antibiotics, and inadequate treatment options for biofilms formed during bacterial infections. Biofilms are complex microbiomes enshrouded in a self-produced extracellular polymeric substance (EPS) that is a primary defense mechanism of the resident microorganisms against antimicrobial agents and the host immune system. In addition to the physical protective EPS barrier, biofilm-resident bacteria exhibit tolerance mechanisms enabling persistence and the establishment of recurrent infections. As current antibiotics and therapeutics are becoming less effective in combating AMR, new innovative technologies are needed to address the growing AMR threat. This perspective article highlights such a product, CMTX-101, a humanized monoclonal antibody that targets a universal component of bacterial biofilms, leading to pathogen-agnostic rapid biofilm collapse and engaging three modes of action—the sensitization of bacteria to antibiotics, host immune enablement, and the suppression of site-specific tissue inflammation. CMTX-101 is a new tool used to enhance the effectiveness of existing, relatively inexpensive first-line antibiotics to fight infections while promoting antimicrobial stewardship.

scholarly journals Emerging Treatment Options for Infections by Multidrug-Resistant Gram-Positive Microorganisms

2020 ◽  
Vol 8 (2) ◽  
pp. 191 ◽  
Author(s):  
Despoina Koulenti ◽  
Elena Xu ◽  
Andrew Song ◽  
Isaac Yin Sum Mok ◽  
Drosos E. Karageorgopoulos ◽  
...  
Keyword(s):  
Safety Profile ◽  
Bacterial Infections ◽  
Antimicrobial Agents ◽  
Treatment Options ◽  
Multidrug Resistant ◽  
Current Treatment ◽  
Multi Drug Resistance ◽  
Gram Positive ◽  
Treatment Regimens ◽  
Gram Positive Bacteria

Antimicrobial agents are currently the mainstay of treatment for bacterial infections worldwide. However, due to the increased use of antimicrobials in both human and animal medicine, pathogens have now evolved to possess high levels of multi-drug resistance, leading to the persistence and spread of difficult-to-treat infections. Several current antibacterial agents active against Gram-positive bacteria will be rendered useless in the face of increasing resistance rates. There are several emerging antibiotics under development, some of which have been shown to be more effective with an improved safety profile than current treatment regimens against Gram-positive bacteria. We will extensively discuss these antibiotics under clinical development (phase I-III clinical trials) to combat Gram-positive bacteria, such as Staphylococcus aureus, Enterococcus faecium and Streptococcus pneumoniae. We will delve into the mechanism of actions, microbiological spectrum, and, where available, the pharmacokinetics, safety profile, and efficacy of these drugs, aiming to provide a comprehensive review to the involved stakeholders.

Corrigendum to “Synthesis of novel 2-aminobenzothiazole derivatives as potential antimicrobial agents with dual DNA gyrase/topoisomerase IV inhibition” [Bioorg. Chem. 94 (2020) 103437]

2020 ◽  
Vol 98 ◽  
pp. 103716
Author(s):  
Magda M.F. Ismail ◽  
Hanan Gaber Abdulwahab ◽  
Eman Samir Nossier ◽  
Nagwan Galal El Menofy ◽  
Basma Abdelhameed Abdelkhalek
Keyword(s):  
Antimicrobial Agents ◽  
Dna Gyrase ◽  
Topoisomerase Iv

scholarly journals In Vitro Evaluation of CBR-2092, a Novel Rifamycin-Quinolone Hybrid Antibiotic: Studies of the Mode of Action in Staphylococcus aureus

2008 ◽  
Vol 52 (7) ◽  
pp. 2313-2323 ◽  
Author(s):  
Gregory T. Robertson ◽  
Eric J. Bonventre ◽  
Timothy B. Doyle ◽  
Qun Du ◽  
Leonard Duncan ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Rna Polymerase ◽  
Mode Of Action ◽  
Bacterial Infections ◽  
Dna Gyrase ◽  
Topoisomerase Iv ◽  
Dna Topoisomerase ◽  
Resistant Variant ◽  
Proven Efficacy

ABSTRACT Rifamycins have proven efficacy in the treatment of persistent bacterial infections. However, the frequency with which bacteria develop resistance to rifamycin agents restricts their clinical use to antibiotic combination regimens. In a program directed toward the synthesis of rifamycins with a lower propensity to elicit resistance development, a series of compounds were prepared that covalently combine rifamycin and quinolone pharmacophores to form stable hybrid antibacterial agents. We describe mode-of-action studies with Staphylococcus aureus of CBR-2092, a novel hybrid that combines the rifamycin SV and 4H-4-oxo-quinolizine pharmacophores. In biochemical studies, CBR-2092 exhibited rifampin-like potency as an inhibitor of RNA polymerase, was an equipotent (balanced) inhibitor of DNA gyrase and DNA topoisomerase IV, and retained activity against a prevalent quinolone-resistant variant. Macromolecular biosynthesis studies confirmed that CBR-2092 has rifampin-like effects on RNA synthesis in rifampin-susceptible strains and quinolone-like effects on DNA synthesis in rifampin-resistant strains. Studies of mutant strains that exhibited reduced susceptibility to CBR-2092 further substantiated RNA polymerase as the primary cellular target of CBR-2092, with DNA gyrase and DNA topoisomerase IV being secondary and tertiary targets, respectively, in strains exhibiting preexisting rifampin resistance. In contrast to quinolone comparator agents, no strains with altered susceptibility to CBR-2092 were found to exhibit changes consistent with altered efflux properties. The combined data indicate that CBR-2092 may have potential utility in monotherapy for the treatment of persistent S. aureus infections.

Antimicrobial Resistance in the Intensive Care Unit

2016 ◽  
Vol 32 (1) ◽  
pp. 25-37 ◽  
Author(s):  
Shawn H. MacVane
Keyword(s):  
Intensive Care ◽  
Antimicrobial Resistance ◽  
Bacterial Infections ◽  
Antimicrobial Agents ◽  
Treatment Options ◽  
Hospital Costs ◽  
High Morbidity ◽  
Gram Negative Bacteria ◽  
Gram Negative ◽  
Gram Negative Organisms

Bacterial infections are a frequent cause of hospitalization, and nosocomial infections are an increasingly common condition, particularly within the acute/critical care setting. Infection control practices and new antimicrobial development have primarily focused on gram-positive bacteria; however, in recent years, the incidence of infections caused by gram-negative bacteria has risen considerably in intensive care units. Infections caused by multidrug-resistant (MDR) gram-negative organisms are associated with high morbidity and mortality, with significant direct and indirect costs resulting from prolonged hospitalizations due to antibiotic treatment failures. Of particular concern is the increasing prevalence of antimicrobial resistance to β-lactam antibiotics (including carbapenems) among Pseudomonas aeruginosa and Acinetobacter baumannii and, recently, among pathogens of the Enterobacteriaceae family. Treatment options for infections caused by these pathogens are limited. Antimicrobial stewardship programs focus on optimizing the appropriate use of currently available antimicrobial agents with the goals of improving outcomes for patients with infections caused by MDR gram-negative organisms, slowing the progression of antimicrobial resistance, and reducing hospital costs. Newly approved treatment options are available, such as β-lactam/β-lactamase inhibitor combinations, which significantly extend the armamentarium against MDR gram-negative bacteria.

scholarly journals Alteration of Escherichia coli Topoisomerase IV to Novobiocin Resistance

2003 ◽  
Vol 47 (3) ◽  
pp. 941-947 ◽  
Author(s):  
Christine D. Hardy ◽  
Nicholas R. Cozzarelli
Keyword(s):  
Escherichia Coli ◽  
Antimicrobial Agents ◽  
Wide Spectrum ◽  
Dna Gyrase ◽  
Primary Role ◽  
Topoisomerase Iv ◽  
Negative Supercoiling ◽  
A Site

ABSTRACT DNA gyrase and topoisomerase IV (topo IV) are the two essential type II topoisomerases of Escherichia coli. Gyrase is responsible for maintaining negative supercoiling of the bacterial chromosome, whereas topo IV's primary role is in disentangling daughter chromosomes following DNA replication. Coumarins, such as novobiocin, are wide-spectrum antimicrobial agents that primarily interfere with DNA gyrase. In this work we designed an alteration in the ParE subunit of topo IV at a site homologous to that which confers coumarin resistance in gyrase. This parE mutation renders the encoded topo IV approximately 40-fold resistant to inhibition by novobiocin in vitro and imparts a similar resistance to inhibition of topo IV-mediated relaxation of supercoiled DNA in vivo. We conclude that topo IV is a secondary target of novobiocin and that it is very likely to be inhibited by the same mechanism as DNA gyrase.

Sign in / Sign up

Export Citation Format

Share Document