scholarly journals In Vitro and In Vivo Profiles of ACH-702, an Isothiazoloquinolone, against Bacterial Pathogens

2011 ◽  
Vol 55 (6) ◽  
pp. 2860-2871 ◽  
Author(s):  
Michael J. Pucci ◽  
Steven D. Podos ◽  
Jane A. Thanassi ◽  
Melissa J. Leggio ◽  
Barton J. Bradbury ◽  
...  
Keyword(s):  
Antibacterial Activity ◽  
Dna Replication ◽  
Bacterial Pathogens ◽  
Biological Data ◽  
Topoisomerase Iv ◽  
Gram Positive ◽  
Gram Negative ◽  
Content Type ◽  
Good Antibacterial Activity

ABSTRACTACH-702, a novel isothiazoloquinolone (ITQ), was assessed for antibacterial activity against a panel of Gram-positive and Gram-negative clinical isolates and found to possess broad-spectrum activity, especially against antibiotic-resistant Gram-positive strains, including methicillin-resistantStaphylococcus aureus(MRSA). For Gram-negative bacteria, ACH-702 showed exceptional potency againstHaemophilus influenzae,Moraxella catarrhalis, and aNeisseriasp. but was less active against members of theEnterobacteriaceae. Good antibacterial activity was also evident against several anaerobes as well asLegionella pneumophilaandMycoplasma pneumoniae. Excellent bactericidal activity was observed for ACH-702 against several bacterial pathogens in time-kill assays, and postantibiotic effects (PAEs) of >1 h were evident with both laboratory and clinical strains of staphylococci at 10× MIC and similar in most cases to those observed for moxifloxacin at the same MIC multiple.In vivoefficacy was demonstrated againstS. aureuswith murine sepsis and thigh infection models, with decreases in the number of CFU/thigh equal to or greater than those observed after vancomycin treatment. Macromolecular synthesis assays showed specific dose-dependent inhibition of DNA replication in staphylococci, and biochemical analyses indicated potent dual inhibition of two essential DNA replication enzymes: DNA gyrase and topoisomerase IV. Additional biological data in support of an effective dual targeting mechanism of action include the following: low MIC values (≤0.25 μg/ml) against staphylococcal strains with single mutations in bothgyrAandgrlA(parC), retention of good antibacterial activity (MICs of ≤0.5 μg/ml) against staphylococcal strains with two mutations in bothgyrAandgrlA, and low frequencies for the selection of higher-level resistance (<10−10). These promising initial data support further study of isothiazoloquinolones as potential clinical candidates.

scholarly journals Dynamics ofMycobacterium tuberculosisAg85B Revealed by a Sensitive Enzyme-Linked Immunosorbent Assay

mBio ◽  
2019 ◽  
Vol 10 (2) ◽  
Author(s):  
Joel D. Ernst ◽  
Amber Cornelius ◽  
Miriam Bolz
Keyword(s):  
Protein Secretion ◽  
Immunosorbent Assay ◽  
Bacterial Population ◽  
Enzyme Linked Immunosorbent Assay ◽  
Bacterial Protein ◽  
Gram Positive ◽  
Gram Negative ◽  
Content Type ◽  
Bacterial Proteins

ABSTRACTSecretion of specific proteins contributes to pathogenesis and immune responses in tuberculosis and other bacterial infections, yet the kinetics of protein secretion and fate of secreted proteinsin vivoare poorly understood. We generated new monoclonal antibodies that recognize theMycobacteriumtuberculosissecreted protein Ag85B and used them to establish and characterize a sensitive enzyme-linked immunosorbent assay (ELISA) to quantitate Ag85B in samples generatedin vitroandin vivo. We found that nutritional or culture conditions had little impact on the secretion of Ag85B and that there is considerable variation in Ag85B secretion by distinct strains in theM. tuberculosiscomplex: compared with the commonly used H37Rv strain (lineage 4),Mycobacteriumafricanum(lineage 6) secretes less Ag85B, and two strains from lineage 2 secrete more Ag85B. We also used the ELISA to determine that the rate of secretion of Ag85B is 10- to 100-fold lower than that of proteins secreted by Gram-negative and Gram-positive bacteria, respectively. ELISA quantitation of Ag85B in lung homogenates ofM. tuberculosisH37Rv-infected mice revealed that although Ag85B accumulates in the lungs as the bacterial population expands, the amount of Ag85B per bacterium decreases nearly 10,000-fold at later stages of infection, coincident with the development of T cell responses and arrest of bacterial population growth. These results indicate that bacterial protein secretionin vivois dynamic and regulated, and quantitation of secreted bacterial proteins can contribute to the understanding of pathogenesis and immunity in tuberculosis and other infections.IMPORTANCEBacterial protein secretion contributes to host-pathogen interactions, yet the process and consequences of bacterial protein secretion during infection are poorly understood. We developed a sensitive ELISA to quantitate a protein (termed Ag85B) secreted byM. tuberculosisand used it to find that Ag85B secretion occurs with slower kinetics than for proteins secreted by Gram-positive and Gram-negative bacteria and that accumulation of Ag85B in the lungs is markedly regulated as a function of the bacterial population density. Our results demonstrate that quantitation of bacterial proteins during infection can reveal novel insights into host-pathogen interactions.

Synthesis of new azobenzene dyes clubbed with thiazolidinone moiety and their applications

2020 ◽  
Vol 49 (3) ◽  
pp. 207-214 ◽  
Author(s):  
Hatem E. Gaffer ◽  
Ismail I. Althagafi
Keyword(s):  
Antimicrobial Activity ◽  
Antibacterial Activity ◽  
Proton Nuclear Magnetic Resonance ◽  
Spectral Studies ◽  
Gram Negative Bacteria ◽  
Anticancer Activities ◽  
Gram Positive ◽  
Gram Negative ◽  
Polyester Fabrics ◽  
Content Type

Purpose The purpose of this paper is to synthesize some new azobenzene dyestuffs clubbed with thiazolidinone moiety and their solicitation in dyeing polyester fabrics representing their antibacterial evaluation. Design/methodology/approach Herein, the authors report the synthesis of new thiazolidinone moiety after the coupling of diazotized 4-aminoacetophenone with resorcinol. The newly synthesized dyes were characterized by IR, elemental analysis, mass spectroscopy and proton nuclear magnetic resonance (1H NMR) spectral studies. The characteristics of dyeing of these dyestuffs were evaluated at optimum conditions. Concurrent with dyeing of polyester fabric for synthesized dyes with their antibacterial activity was estimated. Antimicrobial activity of the dyed fabrics at different concentrations was evaluated against gram-positive and gram-negative bacteria. Findings Synthesized azobenzene dyestuffs clubbed with thiazolidinone dyes were applied on polyester fabrics. It was remarked that the modified dyes exhibited better colourfastness properties. Furthermore, the synthesized dyes revealed antimicrobial activity against gram-positive and gram-negative bacteria. Research limitations/implications The synthesized azobenzene dyes for polyester dyeing were not bore earlier. Practical implications The azobenzene dyes were accountable for giving improved colourfastness properties on polyester fabrics. Social implications The synthesized azobenzene derivatives are sensibly expensive and applicable dyes accompanied with good antimicrobial and anticancer activities. Originality/value A common process could be affording textiles of colour and antibacterial assets. The newly synthesized dyes containing thiazolidinone moieties with azobenzene coupler showed interesting disperse colourant for polyester with good antibacterial activity.

Synthesis and in vitro antibacterial activity of novel fluoroalkyl-substituted pyrazolyl oxazolidinones

RSC Advances ◽  
2015 ◽  
Vol 5 (90) ◽  
pp. 73660-73669 ◽  
Author(s):  
Lili Yan ◽  
Jingjing Wu ◽  
Heng Chen ◽  
Shaowu Zhang ◽  
Zhi Wang ◽  
...  
Keyword(s):  
Antibacterial Activity ◽  
Bacterial Pathogens ◽  
Gram Positive ◽  
Good Antibacterial Activity ◽  
In Vitro Antibacterial Activity

A series of novel fluoroalkyl-substituted pyrazole bearing oxazolidinone derivatives were synthesized and evaluated for their antibacterial activity against six Gram-positive bacterial pathogens. Most have good antibacterial activity, three being comparable to linezolid.

scholarly journals In VitroActivity of AZD0914, a Novel Bacterial DNA Gyrase/Topoisomerase IV Inhibitor, against Clinically Relevant Gram-Positive and Fastidious Gram-Negative Pathogens

2015 ◽  
Vol 59 (10) ◽  
pp. 6053-6063 ◽  
Author(s):  
Douglas J. Biedenbach ◽  
Michael D. Huband ◽  
Meredith Hackel ◽  
Boudewijn L. M. de Jonge ◽  
Daniel F. Sahm ◽  
...  
Keyword(s):  
Bacterial Species ◽  
Dna Gyrase ◽  
Species Group ◽  
Coagulase Negative Staphylococci ◽  
Topoisomerase Iv ◽  
Gram Positive ◽  
Bacterial Dna ◽  
Gram Negative ◽  
Content Type

ABSTRACTAZD0914, a new spiropyrimidinetrione bacterial DNA gyrase inhibitor with a novel mode of inhibition, has activity against bacterial species commonly cultured from patient infection specimens, including fluoroquinolone-resistant isolates. This study assessed thein vitroactivity of AZD0914 against key Gram-positive and fastidious Gram-negative clinical isolates collected globally in 2013. AZD0914 demonstrated potent activity, with MIC90s for AZD0914 of 0.25 mg/liter againstStaphylococcus aureus(n= 11,680), coagulase-negative staphylococci (n= 1,923), streptococci (n= 4,380), andMoraxella catarrhalis(n= 145), 0.5 mg/liter againstStaphylococcus lugdunensis(n= 120) andHaemophilus influenzae(n= 352), 1 mg/liter againstEnterococcus faecalis(n= 1,241), and 2 mg/liter againstHaemophilus parainfluenzae(n= 70). The activity againstEnterococcus faeciumwas more limited (MIC90, 8 mg/liter). The spectrum and potency of AZD0914 included fluoroquinolone-resistant isolates in each species group, including methicillin-resistant staphylococci, penicillin-resistant streptococci, vancomycin-resistant enterococci, β-lactamase-producingHaemophilusspp., andM. catarrhalis. Based on thesein vitrofindings, AZD0914 warrants further investigation for its utility against a variety of Gram-positive and fastidious Gram-negative bacterial species.

scholarly journals In VitroAntibacterial Activity of AZD0914, a New Spiropyrimidinetrione DNA Gyrase/Topoisomerase Inhibitor with Potent Activity against Gram-Positive, Fastidious Gram-Negative, and Atypical Bacteria

2014 ◽  
Vol 59 (1) ◽  
pp. 467-474 ◽  
Author(s):  
Michael D. Huband ◽  
Patricia A. Bradford ◽  
Linda G. Otterson ◽  
Gregory S. Basarab ◽  
Amy C. Kutschke ◽  
...  
Keyword(s):  
Antibacterial Activity ◽  
Legionella Pneumophila ◽  
Bacterial Species ◽  
Dna Gyrase ◽  
Cross Resistance ◽  
Gram Positive ◽  
Gram Negative ◽  
Content Type ◽  
Topoisomerase Inhibitor

ABSTRACTAZD0914 is a new spiropyrimidinetrione bacterial DNA gyrase/topoisomerase inhibitor with potentin vitroantibacterial activity against key Gram-positive (Staphylococcus aureus,Staphylococcus epidermidis,Streptococcus pneumoniae,Streptococcus pyogenes, andStreptococcus agalactiae), fastidious Gram-negative (Haemophilus influenzaeandNeisseria gonorrhoeae), atypical (Legionella pneumophila), and anaerobic (Clostridium difficile) bacterial species, including isolates with known resistance to fluoroquinolones. AZD0914 works via inhibition of DNA biosynthesis and accumulation of double-strand cleavages; this mechanism of inhibition differs from those of other marketed antibacterial compounds. AZD0914 stabilizes and arrests the cleaved covalent complex of gyrase with double-strand broken DNA under permissive conditions and thus blocks religation of the double-strand cleaved DNA to form fused circular DNA. Whereas this mechanism is similar to that seen with fluoroquinolones, it is mechanistically distinct. AZD0914 exhibited low frequencies of spontaneous resistance inS. aureus, and if mutants were obtained, the mutations mapped togyrB. Additionally, no cross-resistance was observed for AZD0914 against recent bacterial clinical isolates demonstrating resistance to fluoroquinolones or other drug classes, including macrolides, β-lactams, glycopeptides, and oxazolidinones. AZD0914 was bactericidal in both minimum bactericidal concentration andin vitrotime-kill studies. Inin vitrocheckerboard/synergy testing with 17 comparator antibacterials, only additivity/indifference was observed. The potentin vitroantibacterial activity (including activity against fluoroquinolone-resistant isolates), low frequency of resistance, lack of cross-resistance, and bactericidal activity of AZD0914 support its continued development.

scholarly journals Nybomycin Inhibits both Fluoroquinolone-Sensitive and Fluoroquinolone-Resistant Escherichia coli DNA Gyrase

2021 ◽  
Vol 65 (5) ◽  
Author(s):  
Dmitrii I. Shiriaev ◽  
Alina A. Sofronova ◽  
Ekaterina A. Berdnikovich ◽  
Dmitrii A. Lukianov ◽  
Ekaterina S. Komarova ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Bacterial Species ◽  
Dna Gyrase ◽  
Resistant Bacteria ◽  
Mutant Form ◽  
Wild Type ◽  
Topoisomerase Iv ◽  
Gram Positive ◽  
Gram Negative ◽  
Content Type

ABSTRACT Bacterial type II topoisomerases, DNA gyrase and topoisomerase IV, are targets of many antibiotics, including fluoroquinolones (FQs). Unfortunately, a number of bacterial species easily acquire resistance to FQs by mutations in either DNA gyrase or topoisomerase IV genes. The emergence of resistant pathogenic strains is a global problem in health care; therefore, identifying alternative pathways to thwart their persistence is the current frontier in drug discovery. Nybomycins are an attractive class of compounds, reported to be “reverse antibiotics” that selectively inhibit growth of some Gram-positive FQ-resistant bacteria by targeting the mutant form of DNA gyrase while being inactive against wild-type strains with FQ-sensitive gyrases. The strong “reverse” effect was demonstrated only for a few Gram-positive organisms resistant to FQs due to the S83L/I mutation in the GyrA subunit of DNA gyrase. However, the activity of nybomycins has not been extensively explored among Gram-negative species. Here, we observed that in a ΔtolC strain of the Gram-negative Escherichia coli with enhanced permeability, wild-type gyrase and a GyrA S83L mutant, resistant to fluoroquinolones, are similarly sensitive to nybomycin.

Combination Therapy for Bacterial Pathogens: Naturally Derived Antimicrobial Drugs Augmented with Ulva lactuca Extract

2021 ◽  
Vol 21 ◽  
Author(s):  
Nilushi Indika Bamunuarachchi ◽  
Fazlurrahman Khan ◽  
Young-Mog Kim
Keyword(s):  
Antibacterial Activity ◽  
Pathogenic Bacteria ◽  
Inhibitory Concentration ◽  
Bacterial Pathogens ◽  
Dilution Method ◽  
Gram Positive ◽  
Antimicrobial Drugs ◽  
Gram Negative ◽  
Hexane Extracts ◽  
Conventional Antibiotics

Background: With the growing incidence of microbial pathogenesis, several alternative strategies have been developed. The number of treatments using naturally (e.g., plants, algae, fungi, bacteria, and animals) derived compounds has increased. Importantly, marine-derived products have become a promising and effective approach to combat the antibiotic resistance properties developed by bacterial pathogens. Furthermore, augmenting the sub-inhibitory concentration of the naturally-derived antimicrobial compounds (e.g., hydroxycinnamic acids, terpenes, marine-derived polysaccharides, phenolic compounds) into the naturally derived extracts as a combination therapy to treat the bacterial infection has not been well studied. Objective: The present study was aimed to prepare green algae Ulva lactuca extract and evaluate its antibacterial activity towards Gram-positive and Gram-negative human pathogenic bacteria. Also, revitalize the antibacterial efficiency of the naturally-derived antimicrobial drugs and conventional antibiotics by augmenting their sub-MIC to the U. lactuca extracts. Methods: Extraction was done using a different organic solvent, and its antibacterial activity was tested towards Gram-positive and Gram-negative pathogens. The minimum inhibitory concentration (MIC) of U. lactuca extracts has been determined towards pathogenic bacteria using the micro broth dilution method. The viable cell counting method was used to determine the minimum bactericidal concentration (MBC). The fractional inhibitory concentration (FIC) assay was utilized to examine the combinatorial impact of sub-MIC of two antibacterial drugs using the micro broth dilution method. The chemical components of the extract were analyzed by GC-MS analysis. Results: Among all the extracts, n-hexane extract was found to show effective antibacterial activity towards tested pathogens with the lowest MIC and MBC value. Furthermore, the n-hexane extracts have also been used to enhance the efficacy of the naturally-derived (derived from plants and marine organisms) compounds and conventional antibiotics at their sub-inhibitory concentrations. Most of the tested antibiotics and natural drugs at their sub-MIC were found to exhibit synergistic and additive antibacterial activity towards the tested bacterial pathogens. Conclusions: The augmenting of U. lactuca n-hexane extracts resulted in synergistic and additive bactericidal effects on Gram-positive and Gram-negative human pathogenic bacteria. The present study shows a new alternative strategy to revitalize the antimicrobial activity of naturally derived compounds for treating human bacterial pathogens.

scholarly journals In VitroActivity of Plazomicin against Gram-Negative and Gram-Positive Bacterial Pathogens Isolated from Patients in Canadian Hospitals from 2013 to 2017 as Part of the CANWARD Surveillance Study

2018 ◽  
Vol 63 (1) ◽  
Author(s):  
Andrew Walkty ◽  
James A. Karlowsky ◽  
Melanie R. Baxter ◽  
Heather J. Adam ◽  
George G. Zhanel
Keyword(s):  
Antimicrobial Agents ◽  
Bacterial Pathogens ◽  
Multidrug Resistant ◽  
Surveillance Study ◽  
Gram Positive ◽  
Gram Negative ◽  
Content Type ◽  
Microdilution Method ◽  
Broth Microdilution Method

ABSTRACTThe Clinical and Laboratory Standards Institute (CLSI) broth microdilution method was used to evaluate thein vitroactivities of plazomicin and comparator antimicrobial agents against 7,712 Gram-negative and 4,481 Gram-positive bacterial pathogens obtained from 2013 to 2017 from patients in Canadian hospitals as part of the CANWARD Surveillance Study. Plazomicin demonstrated potentin vitroactivity againstEnterobacteriaceae(MIC90≤ 1 µg/ml for all species tested exceptProteus mirabilisandMorganella morganii), including aminoglycoside-nonsusceptible, extended-spectrum β-lactamase (ESBL)-positive, and multidrug-resistant (MDR) isolates. Plazomicin was equally active against methicillin-susceptible and methicillin-resistant isolates ofStaphylococcus aureus.

scholarly journals Kibdelomycin Is a Bactericidal Broad-Spectrum Aerobic Antibacterial Agent

2015 ◽  
Vol 59 (6) ◽  
pp. 3474-3481 ◽  
Author(s):  
Sheo B. Singh ◽  
Priya Dayananth ◽  
Carl J. Balibar ◽  
Charles G. Garlisi ◽  
Jun Lu ◽  
...  
Keyword(s):  
Broad Spectrum ◽  
Bacterial Resistance ◽  
Selective Inhibition ◽  
Cross Resistance ◽  
Topoisomerase Iv ◽  
Gram Positive ◽  
Entry Barrier ◽  
Strong Activity ◽  
Gram Negative ◽  
Content Type

ABSTRACTBacterial resistance to antibiotics continues to grow and pose serious challenges, while the discovery rate for new antibiotics declines. Kibdelomycin is a recently discovered natural-product antibiotic that inhibits bacterial growth by inhibiting the bacterial DNA replication enzymes DNA gyrase and topoisomerase IV. It was reported to be a broad-spectrum aerobic Gram-positive agent with selective inhibition of the anaerobic bacteriumClostridium difficile. We have extended the profiling of kibdelomycin by using over 196 strains of Gram-positive and Gram-negative aerobic pathogens recovered from worldwide patient populations. We report the MIC50s, MIC90s, and bactericidal activities of kibdelomycin. We confirm the Gram-positive spectrum and report for the first time that kibdelomycin shows strong activity (MIC90, 0.125 μg/ml) against clinical strains of the Gram-negative nonfermenterAcinetobacter baumanniibut only weak activity againstPseudomonas aeruginosa. We confirm that well-characterized resistant strains ofStaphylococcus aureusandStreptococcus pneumoniaeshow no cross-resistance to kibdelomycin and quinolones and coumarin antibiotics. We also show that kibdelomycin is not subject to efflux inPseudomonas, though it is inEscherichia coli, and it is generally affected by the outer membrane permeability entry barrier in the nonfermentersP. aeruginosaandA. baumannii, which may be addressable by structure-based chemical modification.

scholarly journals Efficacy of Humanized Exposures of Cefiderocol (S-649266) against a Diverse Population of Gram-Negative Bacteria in a Murine Thigh Infection Model

2017 ◽  
Vol 61 (11) ◽  
Author(s):  
Marguerite L. Monogue ◽  
Masakatsu Tsuji ◽  
Yoshinori Yamano ◽  
Roger Echols ◽  
David P. Nicolau
Keyword(s):  
Antibacterial Activity ◽  
Multidrug Resistant ◽  
Infection Model ◽  
Gram Negative Bacteria ◽  
Diverse Population ◽  
Gram Negative ◽  
Content Type ◽  
Log Reduction

ABSTRACT Cefiderocol (S-649266) is a novel siderophore cephalosporin with potent in vitro activity against clinically encountered multidrug-resistant (MDR) Gram-negative isolates; however, its spectrum of antibacterial activity against these difficult-to-treat isolates remains to be fully explored in vivo. Here, we evaluated the efficacy of cefiderocol humanized exposures in a neutropenic murine thigh model to support a suitable MIC breakpoint. Furthermore, we compared cefiderocol's efficacy with humanized exposures of meropenem and cefepime against a subset of these phenotypically diverse isolates. Ninety-five Gram-negative isolates were studied. Efficacy was determined as the change in log10 CFU at 24 h compared with 0-h controls. Bacterial stasis or ≥1 log reduction in 67 isolates with MICs of ≤4 μg/ml was noted in 77, 88, and 85% of Enterobacteriaceae, Acinetobacter baumannii, and Pseudomonas aeruginosa, respectively. For isolates with MICs of ≥8 μg/ml, bacterial stasis or ≥1 log10 reduction was observed in only 2 of 28 (8 Enterobacteriaceae, 19 A. baumannii, and 1 P. aeruginosa) strains. Against highly resistant meropenem and cefepime organisms, cefiderocol maintained its in vivo efficacy. Overall, humanized exposures of cefiderocol produced similar reductions in bacterial density for organisms with MICs of ≤4 μg/ml, whereas isolates with MICs of ≥8 μg/ml generally displayed bacterial growth in the presence of the compound. Data derived in the current study will assist with the delineation of MIC susceptibility breakpoints for cefiderocol against these important nosocomial Gram-negative pathogens; however, additional clinical data are required to substantiate these observations.

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