scholarly journals In Vitro Resistance against DNA Gyrase Inhibitor SPR719 in Mycobacterium avium and Mycobacterium abscessus

2022 ◽  
Author(s):  
Wassihun Wedajo Aragaw ◽  
Nicole Cotroneo ◽  
Suzanne Stokes ◽  
Michael Pucci ◽  
Ian Critchley ◽  
...  
Keyword(s):  
Mycobacterium Avium ◽  
Dna Gyrase ◽  
Mycobacterium Abscessus ◽  
Drug Candidates ◽  
New Antibiotics ◽  
Novel Drug ◽  
Emergence Of Resistance

Clinical emergence of resistance to new antibiotics affects their utility. Characterization of in vitro resistance is a first step in the profiling of resistance properties of novel drug candidates.

scholarly journals In Vitro Characterization of the Antibacterial Spectrum of Novel Bacterial Type II Topoisomerase Inhibitors of the Aminobenzimidazole Class

2006 ◽  
Vol 50 (4) ◽  
pp. 1228-1237 ◽  
Author(s):  
Nagraj Mani ◽  
Christian H. Gross ◽  
Jonathan D. Parsons ◽  
Brian Hanzelka ◽  
Ute Müh ◽  
...  
Keyword(s):  
Bacterial Resistance ◽  
Wide Spectrum ◽  
Dna Gyrase ◽  
Antibacterial Activities ◽  
Mechanisms Of Action ◽  
Fluoroquinolone Resistance ◽  
Topoisomerase Iv ◽  
Low Frequencies

ABSTRACT Antibiotics with novel mechanisms of action are becoming increasingly important in the battle against bacterial resistance to all currently used classes of antibiotics. Bacterial DNA gyrase and topoisomerase IV (topoIV) are the familiar targets of fluoroquinolone and coumarin antibiotics. Here we present the characterization of two members of a new class of synthetic bacterial topoII ATPase inhibitors: VRT-125853 and VRT-752586. These aminobenzimidazole compounds were potent inhibitors of both DNA gyrase and topoIV and had excellent antibacterial activities against a wide spectrum of problematic pathogens responsible for both nosocomial and community-acquired infections, including staphylococci, streptococci, enterococci, and mycobacteria. Consistent with the novelty of their structures and mechanisms of action, antibacterial potency was unaffected by commonly encountered resistance phenotypes, including fluoroquinolone resistance. In time-kill assays, VRT-125853 and VRT-752586 were bactericidal against Staphylococcus aureus, Streptococcus pneumoniae, Enterococcus faecalis, and Haemophilus influenzae, causing 3-log reductions in viable cells within 24 h. Finally, similar to the fluoroquinolones, relatively low frequencies of spontaneous resistance to VRT-125853 and VRT-752586 were found, a property consistent with their in vitro dual-targeting activities.

scholarly journals Evidence for Inhibition of Topoisomerase 1A by Gold(III) Macrocycles and Chelates TargetingMycobacterium tuberculosisandMycobacterium abscessus

2018 ◽  
Vol 62 (5) ◽  
Author(s):  
Rashmi Gupta ◽  
Carolina Rodrigues Felix ◽  
Matthew P. Akerman ◽  
Kate J. Akerman ◽  
Cathryn A. Slabber ◽  
...  
Keyword(s):  
Mycobacterium Abscessus ◽  
Cross Resistance ◽  
Human Pathogens ◽  
Intrinsic Resistance ◽  
Content Type ◽  
Starting Point ◽  
Scalable Synthesis ◽  
High Level ◽  
Novel Drug

ABSTRACTMycobacterium tuberculosisand the fast-growing speciesMycobacterium abscessusare two important human pathogens causing persistent pulmonary infections that are difficult to cure and require long treatment times. The emergence of drug-resistantM. tuberculosisstrains and the high level of intrinsic resistance ofM. abscessuscall for novel drug scaffolds that effectively target both pathogens. In this study, we evaluated the activity of bis(pyrrolide-imine) gold(III) macrocycles and chelates, originally designed as DNA intercalators capable of targeting human topoisomerase types I and II (Topo1 and Topo2), againstM. abscessusandM. tuberculosis. We identified a total of 5 noncytotoxic compounds active against both mycobacterial pathogens under replicatingin vitroconditions. We chose one of these hits, compound 14, for detailed analysis due to its potent bactericidal mode of inhibition and scalable synthesis. The clinical relevance of this compound was demonstrated by its ability to inhibit a panel of diverseM. tuberculosisandM. abscessusclinical isolates. Prompted by previous data suggesting that compound 14 may target topoisomerase/gyrase enzymes, we demonstrated that it lacked cross-resistance with fluoroquinolones, which target theM. tuberculosisgyrase.In vitroenzyme assays confirmed the potent activity of compound 14 against bacterial topoisomerase 1A (Topo1) enzymes but not gyrase. Novel scaffolds like compound 14 with potent, selective bactericidal activity againstM. tuberculosisandM. abscessusthat act on validated but underexploited targets like Topo1 represent a promising starting point for the development of novel therapeutics for infections by pathogenic mycobacteria.

scholarly journals In vitro characterization of DNA gyrase inhibition by microcin B17 analogs with altered bisheterocyclic sites

2001 ◽  
Vol 98 (14) ◽  
pp. 7712-7717 ◽  
Author(s):  
D. B. Zamble ◽  
D. A. Miller ◽  
J. G. Heddle ◽  
A. Maxwell ◽  
C. T. Walsh ◽  
...  
Keyword(s):  
Dna Gyrase ◽  
In Vitro Characterization ◽  
Microcin B17

scholarly journals Effective Treatment of Mycobacterium avium subsp. hominissuis and Mycobacterium abscessus Species Infections in Macrophages, Biofilm, and Mice by Using Liposomal Ciprofloxacin

2018 ◽  
Vol 62 (10) ◽  
Author(s):  
James D. Blanchard ◽  
Valerie Elias ◽  
David Cipolla ◽  
Igor Gonda ◽  
Luiz E. Bermudez
Keyword(s):  
Effective Treatment ◽  
Mouse Models ◽  
Mycobacterium Avium ◽  
Nontuberculous Mycobacteria ◽  
Mycobacterium Abscessus ◽  
Content Type ◽  
Number Of Individuals ◽  
Intranasal Instillation

ABSTRACT Nontuberculous mycobacteria (NTM) affect an increasing number of individuals worldwide. Infection with these organisms is more common in patients with chronic lung conditions, and treatment is challenging. Quinolones, such as ciprofloxacin, have been used to treat patients, but the results have not been encouraging. In this report, we evaluate novel formulations of liposome-encapsulated ciprofloxacin (liposomal ciprofloxacin) in vitro and in vivo. Its efficacy against Mycobacterium avium and Mycobacterium abscessus was examined in macrophages, in biofilms, and in vivo using intranasal instillation mouse models. Liposomal ciprofloxacin was significantly more active than free ciprofloxacin against both pathogens in macrophages and biofilms. When evaluated in vivo, treatment with the liposomal ciprofloxacin formulations was associated with significant decreases in the bacterial loads in the lungs of animals infected with M. avium and M. abscessus. In summary, topical delivery of liposomal ciprofloxacin in the lung at concentrations greater than those achieved in the serum can be effective in the treatment of NTM, and further evaluation is warranted.

In Vitro Efficacy of Free and Nanoparticle Formulations of Gallium(III) meso-Tetraphenylporphyrine against Mycobacterium avium and Mycobacterium abscessus and Gallium Biodistribution in Mice

2018 ◽  
Vol 15 (3) ◽  
pp. 1215-1225 ◽  
Author(s):  
Seoung-ryoung Choi ◽  
Bradley E. Britigan ◽  
Barbara Switzer ◽  
Traci Hoke ◽  
David Moran ◽  
...  
Keyword(s):  
Mycobacterium Avium ◽  
Mycobacterium Abscessus

scholarly journals Telithromycin Is Active against Mycobacterium avium in Mice despite Lacking Significant Activity in Standard In Vitro and Macrophage Assays and Is Associated with Low Frequency of Resistance during Treatment

2001 ◽  
Vol 45 (8) ◽  
pp. 2210-2214 ◽  
Author(s):  
Luiz E. Bermudez ◽  
Clark B. Inderlied ◽  
Peter Kolonoski ◽  
Martin Wu ◽  
Priscilla Aralar ◽  
...  
Keyword(s):  
Body Weight ◽  
Mycobacterium Avium ◽  
Day Treatment ◽  
Low Frequency ◽  
Significant Activity ◽  
Aids Patients ◽  
Emergence Of Resistance

ABSTRACT The activity of telithromycin, a new ketolide, was evaluated in vitro and in vivo against Mycobacterium avium complex (MAC) strains. The MIC of telithromycin for several M. aviumisolates obtained from the blood of AIDS patients ranged from 16 to >128 μg/ml (MIC at which 90% of isolates are inhibited, >128 μg/ml), and the compound did show activity in the macrophage system at concentrations greater than 8 or 16 μg/ml, but this was dependent on the MAC strain used. Telithromycin was then administered to mice infected with MAC strain 101 for 4 weeks at doses of 100, 200, or 400 mg/kg of body weight/day. Treatment with 100 and 200 mg/kg/day was bacteriostatic, but at 400 mg/kg/day telithromycin was bactericidal for MAC strains. The frequency of the emergence of resistance to telithromycin was low despite prolonged usage (12 weeks). This study demonstrates that telithromycin is active in vivo against MAC and warrants further evaluation.

scholarly journals Synergistic Activity of Combined NS5A Inhibitors

2015 ◽  
Vol 60 (3) ◽  
pp. 1573-1583 ◽  
Author(s):  
Donald R. O'Boyle ◽  
Peter T. Nower ◽  
Min Gao ◽  
Robert Fridell ◽  
Chunfu Wang ◽  
...  
Keyword(s):  
Cooperative Interaction ◽  
Synergistic Activity ◽  
Replication Complex ◽  
New Class ◽  
Infected Cells ◽  
Inhibitory Potential ◽  
Direct Acting ◽  
Emergence Of Resistance

Daclatasvir (DCV) is a first-in-class hepatitis C virus (HCV) nonstructural 5A replication complex inhibitor (NS5A RCI) that is clinically effective in interferon-free combinations with direct-acting antivirals (DAAs) targeting alternate HCV proteins. Recently, we reported NS5A RCI combinations that enhance HCV inhibitory potentialin vitro, defining a new class of HCV inhibitors termed NS5A synergists (J. Sun, D. R. O’Boyle II, R. A. Fridell, D. R. Langley, C. Wang, S. Roberts, P. Nower, B. M. Johnson F. Moulin, M. J. Nophsker, Y. Wang, M. Liu, K. Rigat, Y. Tu, P. Hewawasam, J. Kadow, N. A. Meanwell, M. Cockett, J. A. Lemm, M. Kramer, M. Belema, and M. Gao, Nature 527:245–248, 2015, doi:10.1038/nature15711). To extend the characterization of NS5A synergists, we tested new combinations of DCV and NS5A synergists against genotype (gt) 1 to 6 replicons and gt 1a, 2a, and 3a viruses. The kinetics of inhibition in HCV-infected cells treated with DCV, an NS5A synergist (NS5A-Syn), or a combination of DCV and NS5A-Syn were distinctive. Similar to activity observed clinically, DCV caused a multilog drop in HCV, followed by rebound due to the emergence of resistance. DCV–NS5A-Syn combinations were highly efficient at clearing cells of viruses, in line with the trend seen in replicon studies. The retreatment of resistant viruses that emerged using DCV monotherapy with DCV–NS5A-Syn resulted in a multilog drop and rebound in HCV similar to the initial decline and rebound observed with DCV alone on wild-type (WT) virus. A triple combination of DCV, NS5A-Syn, and a DAA targeting the NS3 or NS5B protein cleared the cells of viruses that are highly resistant to DCV. Our data support the observation that the cooperative interaction of DCV and NS5A-Syn potentiates both the genotype coverage and resistance barrier of DCV, offering an additional DAA option for combination therapy and tools for explorations of NS5A function.

scholarly journals Design and development of drugs for Alzheimer’s dementia as a protein misfolding disorder

2015 ◽  
Vol 42 (S1) ◽  
pp. S16-S16
Author(s):  
C Barden ◽  
F Meier-Stephenson ◽  
MD Carter ◽  
S Banfield ◽  
EC Diez ◽  
...  
Keyword(s):  
Transgenic Mouse ◽  
Protein Misfolding ◽  
Large Scale ◽  
Beta Amyloid ◽  
Protein Oligomerization ◽  
Drug Candidates ◽  
Pharmacokinetic Properties ◽  
Disease Modifying Agents ◽  
Novel Drug

Background: There are no disease modifying agents for the treatment of Alzheimer’s disease (AD). Pathologically, AD is associated with the misfolding of two peptides: beta-amyloid (plaques) and tau (tangles). Methods: Using large-scale computer simulations, we modelled the misfolding of both beta-amyloid and tau, identifying a common conformational motif (CCM; i.e. an abnormal peptide shape), present in both beta-amyloid and tau, that promotes their misfolding. We screened a library of 11.8 million compounds against this in silico model of protein misfolding, identifying three novel molecular classes of putative therapeutics as anti-protein misfolding agents. We synthesized approximately 400 new chemical entity drug-like molecules in each of these three classes (i.e. 1200 potential drug candidates). These were comprehensively screened in a battery of five in vitro protein oligomerization assays. Selected compounds were next evaluated in the APP/PS1 doubly transgenic mouse model of AD. Results: Two new classes of molecules were identified with the ability to block the oligomerization of both beta-amyloid and tau. These compounds are drug-like with good pharmacokinetic properties and are brain-penetrant. They exhibit excellent efficacy in transgenic mouse models. Conclusion: Computer aided drug design has enabled the discovery of novel drug-like molecules able to inhibit both tau and beta-amyloid misfolding.

scholarly journals Artemisia annua and Artemisia afra extracts exhibit strong bactericidal activity against Mycobacterium tuberculosis

2020 ◽  
Author(s):  
Maria Carla Martini ◽  
Tianbi Zhang ◽  
John T. Williams ◽  
Robert B. Abramovitch ◽  
Pamela J. Weathers ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Bactericidal Activity ◽  
Artemisia Annua ◽  
Multidrug Resistant ◽  
Mycobacterium Abscessus ◽  
Major Barrier ◽  
Treatment Regimens ◽  
Tb Treatment ◽  
Emergence Of Resistance

ABSTRACTEthnopharmacological relevanceEmergence of drug-resistant and multidrug-resistant Mycobacterium tuberculosis (Mtb) strains is a major barrier to tuberculosis (TB) eradication, as it leads to longer treatment regimens and in many cases treatment failure. Thus, there is an urgent need to explore new TB drugs and combinations, in order to shorten TB treatment and improve outcomes. Here, we evaluate the potential of two medicinal plants, Artemisia annua, a natural source of artemisinin (AN), and Artemisia afra, as sources of novel antitubercular agents.Aim of the studyOur goal was to measure the activity of A. annua and A. afra extracts against Mtb as potential natural and inexpensive therapies for TB treatment, or as sources of compounds that could be further developed into effective treatments.Materials and MethodsThe minimum inhibitory concentrations (MICs) of A. annua and A. afra dichloromethane extracts were determined, and concentrations above the MICs were used to evaluate their ability to kill Mtb and Mycobacterium abscessus in vitro.ResultsPrevious studies showed that A. annua and A. afra inhibit Mtb growth. Here, we show for the first time that Artemisia extracts have a strong bactericidal activity against Mtb. The killing effect of A. annua was much stronger than equivalent concentrations of pure AN, suggesting that A. annua extracts kill Mtb through a combination of AN and additional compounds. A. afra, which produces very little AN, displayed bactericidal activity against Mtb that was substantial but weaker than that of A. annua. In addition, we measured the activity of Artemisia extracts against Mycobacterium abscessus. Interestingly, we observed that while A. annua is not bactericidal, it inhibits growth of M. abscessus, highlighting the potential of this plant in combinatory therapies to treat M. abscessus infections.ConclusionOur results indicate that Artemisia extracts have an enormous potential for treatment of TB and M. abscessus infections, and that these plants contain bactericidal compounds in addition to AN. Combination of extracts with existing antibiotics may not only improve treatment outcomes but also reduce the emergence of resistance to other drugs.

Sign in / Sign up

Export Citation Format

Share Document