scholarly journals Antibacterial Activity of Ceftizoxime Against Gram Negative Enteric Bacteria in vitro and in vivo

1989 ◽  
Vol 6 (1) ◽  
pp. 59
Author(s):  
Woo Mok Byun ◽  
Jae Chun Chang ◽  
Bok Hwan Park ◽  
Hee Sun Kim ◽  
Sung Kwang Kim
Keyword(s):  
Antibacterial Activity ◽  
Enteric Bacteria ◽  
Gram Negative

Synthetic Studies with the Brevicidine and Laterocidine Lipopeptide Antibiotics Including Analogues with Enhanced Properties and in vivo Efficacy

2022 ◽  
Author(s):  
Karol Al-Ayed ◽  
Ross D. Ballantine ◽  
Michael Hoekstra ◽  
Samantha Bann ◽  
Charlotte Wesseling ◽  
...  
Keyword(s):  
Antibacterial Activity ◽  
Solid Phase ◽  
Hydrolytic Stability ◽  
Attractive Alternative ◽  
Vitro Assay ◽  
Gram Negative ◽  
Lipopeptide Antibiotics ◽  
Synthetic Routes

Brevicidine and laterocidine are two recently discovered lipopeptide antibiotics with promising antibacterial activity. Possessing a macrocyclic core, multiple positive charges, and a lipidated N-terminus, these lipopeptides exhibit potent and selective activity against Gram-negative pathogens, including polymyxin-resistant isolates. Given the low amounts of brevicidine and laterocidine accessible by fermentation of the producing microorganisms, synthetic routes to these lipopeptides present an attractive alternative. We here report the convenient solid-phase syntheses of both brevicidine and laterocidine and confirm their potent anti-Gram-negative activities. The synthetic routes developed also provide convenient access to novel structural analogues of both brevicidine and laterocidine that display improved hydrolytic stability while maintaining potent antibacterial activity in both in vitro assay and in vivo infection models.

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.

scholarly journals Syntheses and antibacterial activity of novel 6-fluoro-7-(gem-disubstituted piperazin-1-yl)-quinolines

1992 ◽  
Vol 70 (5) ◽  
pp. 1328-1337 ◽  
Author(s):  
Daniel T. W. Chu ◽  
Akiyo K. Claiborne ◽  
Jacob J. Clement ◽  
Jacob J. Plattner
Keyword(s):  
Antibacterial Activity ◽  
Chemical Synthesis ◽  
Antibacterial Agents ◽  
Gram Positive ◽  
Gram Negative ◽  
Gram Negative Organisms

A series of quinoline and naphthyridine antibacterial agents possessing an acyclic or cyclic gem-disubstituted piperazine substituent at the C-7 position have been prepared and evaluated in vitro and in vivo for antibacterial activity against a variety of Gram-positive and Gram-negative organisms. They are, however, not as active as quinolones or naphthyridines with a monosubstituted piperazine substituent at C-7. The chemical synthesis of these derivatives is also described.

scholarly journals Comparative analysis of the phytochemical and antibacterial activity of the root extracts of Euphorbia heterophylla and Vitellaria paradoxa

2021 ◽  
Vol 22 (4) ◽  
pp. 504-514
Author(s):  
U.M. Oyedum ◽  
F.A. Kuta ◽  
S.A. Garba ◽  
S.O. Enejiyon
Keyword(s):  
Antibacterial Activity ◽  
Inbred Mice ◽  
Enteric Bacteria ◽  
Antibacterial Activities ◽  
Activité Antibactérienne ◽  
Phytochemical Analysis ◽  
Vitellaria Paradoxa ◽  
Crude Extracts

Background: Over time, herbal plants and their various components have been major sources of therapeutic medicine for man. A comparative study was carried out to determine the phytochemical components and antibacterial activities of the different crude extracts of Euphorbia heterophylla and Vitellaria paradoxa roots on four enteric bacteria; Salmonella typhi, Shigella flexneri, Escherichia coli and Proteus vulgaris.Methodology: Root samples of E. heterophylla and V. paradoxa were collected, washed, air dried and processed to fine powder in the microbiology laboratory of Federal University of Technology, Minna, Nigeria. Crude extract of the root samples was done by the cold maceration technique using four solvents (chloroform, methanol, petroleum ether and water). Phytochemical analysis of the extracts was done using previously described technique, and in vitro antibacterial activities of different concentrations of the extracts (50-200 mg/ml) and a standard antibiotic (ciprofloxacin) were tested on four enteric bacteria (S. typhi, S. flexneri, E. coli, P. vulgaris) by the agar diffusion test. In vivo antibacterial activities of the two plants were also tested by daily oral administration of 2000 mg/kg bodyweight (for 7 days) of each extract on inbred mice infected through intraperitoneal inoculation of an infective dose of each of the four enteric bacteria. Data were computed as mean ± standard error and analysed by the Statistical Analysis System (SAS) version 9.4. Associations between variables were determined using analysis of variance (ANOVA), with p < 0.05 considered as significant value.Results: Phytochemical analysis of the crude extracts of both plants revealed the presence of cardiac glycosides, saponins, alkaloids, flavonoids, and tannins but V. paradoxa contain more carbohydrates and starch, and less phlobatannins, compared to E. heterophylla. In vitro assay showed dose-dependent antibacterial activity of the methanol, aqueous and chloroform (but not petroleum ether) extracts of the two plant roots. The in vitro antibacterial activities of the different extracts of V. paradoxica extracts were significantly higher (higher mean diameters of inhibition zones) than those of E. heterophylla (p<0.05), and methanol extracts gave the highest antibacterial effects. However, the root extract of E. heterophylla gave a higher antibacterial activity with the in vivo assay on inbred mice than V. paradoxa, and methanol extracts of the two plant extracts gave the highest in vivo activity, followed by aqueous extract and least activity was obtained with the chloroform extract.Conclusion: Crude extracts of E. heterophylla and V. paradoxa roots produce antibacterial activity against enteric Gram-negative bacteria pathogens involved in diarrhoea illnesses. Further researches should be directed towards isolation and characterization of the active compounds in the crude extracts.   French title: Analyse comparative de l'activité phytochimique et antibactérienne des extraits de racines d'Euphorbia heterophylla et de Vitellaria paradoxa Contexte: Au fil du temps, les plantes médicinales et leurs divers composants ont été une source majeure de médecine thérapeutique pour l'homme. Une étude comparative a été réalisée pour déterminer les composants phytochimiques et les activités antibactériennes des différents extraits bruts de racines d'Euphorbia heterophylla et de Vitellaria paradoxa sur quatre bactéries entériques; Salmonella typhi, Shigella flexneri, Escherichia coli et Proteus vulgaris. Méthodologie: Des échantillons de racines d'E. heterophylla et de V. paradoxa ont été collectés, lavés, séchés à l'air et transformés en poudre fine dans le laboratoire de microbiologie de l'Université fédérale de technologie, Minna, Nigéria. L'extraction brute des échantillons de racines a été réalisée par la technique de macération à froid en utilisant quatre solvants (chloroforme, méthanol, éther de pétrole et eau). L'analyse phytochimique des extraits a été effectuée en utilisant la technique décrite précédemment, et les activités antibactériennes in vitro de différentes concentrations des extraits (50-200 mg/ml) et d'un antibiotique standard (ciprofloxacine) ont été testées sur quatre bactéries entériques (S. typhi, S. flexneri, E. coli, P. vulgaris) par le test de diffusion sur gélose. Les activités  antibactériennes in vivo des deux plantes ont également été testées par administration orale quotidienne de 2000 mg/kg de poids corporel (pendant 7 jours) de chaque extrait sur des souris consanguines infectées par inoculation intrapéritonéale d'une dose infectieuse de chacune des quatre bactéries entériques. Les données ont été calculées en tant que moyenne ± erreur standard et analysées par le système d'analyse statistique (SAS) version 9.4. Les associations entre les variables ont été déterminées à l'aide d'une analyse de variance (ANOVA), avec p < 0,05 considéré comme une valeur significative. Résultats: L'analyse phytochimique des extraits bruts des deux plantes a révélé la présence de glycosides cardiaques, de saponines, d'alcaloïdes, de flavonoïdes et de tanins mais V. paradoxa contient plus de glucides et d'amidon, et moins de phlobatannins, par rapport à E. heterophylla. Un essai in vitro a montré une activité antibactérienne dose-dépendante des extraits au méthanol, aqueux et au chloroforme (mais pas à l'éther de pétrole) des deux racines des plantes. Les activités antibactériennes in vitro des différents extraits d'extraits de V. paradoxica étaient significativement plus élevées (diamètres moyens des zones d'inhibition plus élevés) que celles d'E. heterophylla (p<0,05), et les extraits au méthanol ont donné les effets antibactériens les plus élevés. Cependant, l'extrait de racine d'E. heterophylla a donné une activité antibactérienne plus élevée avec le test in vivo sur des souris consanguines que V. paradoxa, et les extraits au méthanol des deux extraits de plantes ont donné l'activité in vivo la plus élevée, suivie par l'extrait aqueux et l'activité la plus faible a été obtenu avec l'extrait chloroformique. Conclusion: Des extraits bruts de racines d'E. heterophylla et de V. paradoxa produisent une activité antibactérienne contre les bactéries pathogènes entériques à Gram négatif impliquées dans les maladies diarrhéiques. D'autres recherches devraient être dirigées vers l'isolement et la caractérisation des composés actifs dans les extraits bruts.

scholarly journals Characterizing the Antimicrobial Activity of N2,N4-Disubstituted Quinazoline-2,4-Diamines toward Multidrug-Resistant Acinetobacter baumannii

2017 ◽  
Vol 61 (6) ◽  
Author(s):  
Renee Fleeman ◽  
Kurt S. Van Horn ◽  
Megan M. Barber ◽  
Whittney N. Burda ◽  
David L. Flanigan ◽  
...  
Keyword(s):  
Antibacterial Activity ◽  
Acinetobacter Baumannii ◽  
Alkyl Substituent ◽  
Fold Increase ◽  
Multidrug Resistant ◽  
Antibiofilm Activity ◽  
Gram Negative ◽  
Content Type

ABSTRACT We previously reported a series of N 2,N 4-disubstituted quinazoline-2,4-diamines as dihydrofolate reductase inhibitors with potent in vitro and in vivo antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA) strains. In this work, we extended our previous study to the Gram-negative pathogen Acinetobacter baumannii. We determined that optimized N 2,N 4-disubstituted quinazoline-2,4-diamines are strongly antibacterial against multidrug-resistant A. baumannii strains when the 6-position is replaced with a halide or an alkyl substituent. Such agents display potent antibacterial activity, with MICs as low as 0.5 μM, while proving to be strongly bactericidal. Interestingly, these compounds also possess the potential for antibiofilm activity, eradicating 90% of cells within a biofilm at or near MICs. Using serial passage assays, we observed a limited capacity for the development of resistance toward these molecules (4-fold increase in MIC) compared to existing folic acid synthesis inhibitors, such as trimethoprim (64-fold increase) and sulfamethoxazole (128-fold increase). We also identified limited toxicity toward human cells, with 50% lethal doses (LD50s) of ≤23 μM for lead agents 4 and 5. Finally, we demonstrated that our lead agents have excellent in vivo efficacy, with lead agent 5 proving more efficacious than tigecycline in a murine model of A. baumannii infection (90% survival versus 66%), despite being used at a lower dose (2 versus 30 mg kg−1). Together, our results demonstrate that N 2,N 4-disubstituted quinazoline-2,4-diamines have strong antimicrobial and antibiofilm activities against both Gram-positive organisms and Gram-negative pathogens, suggesting strong potential for their development as antibacterial agents.

scholarly journals The Multifunctional Sactipeptide Ruminococcin C1 Displays Potent Antibacterial Activity In Vivo as Well as Other Beneficial Properties for Human Health

2021 ◽  
Vol 22 (6) ◽  
pp. 3253
Author(s):  
Clarisse Roblin ◽  
Steve Chiumento ◽  
Cédric Jacqueline ◽  
Eric Pinloche ◽  
Cendrine Nicoletti ◽  
...  
Keyword(s):  
Antibacterial Activity ◽  
Human Health ◽  
Biological Activities ◽  
Resistant Bacteria ◽  
Modified Peptides ◽  
The 1960S ◽  
Conventional Antibiotics ◽  
Clinical Potential

The world is on the verge of a major antibiotic crisis as the emergence of resistant bacteria is increasing, and very few novel molecules have been discovered since the 1960s. In this context, scientists have been exploring alternatives to conventional antibiotics, such as ribosomally synthesized and post-translationally modified peptides (RiPPs). Interestingly, the highly potent in vitro antibacterial activity and safety of ruminococcin C1, a recently discovered RiPP belonging to the sactipeptide subclass, has been demonstrated. The present results show that ruminococcin C1 is efficient at curing infection and at protecting challenged mice from Clostridium perfringens with a lower dose than the conventional antibiotic vancomycin. Moreover, antimicrobial peptide (AMP) is also effective against this pathogen in the complex microbial community of the gut environment, with a selective impact on a few bacterial genera, while maintaining a global homeostasis of the microbiome. In addition, ruminococcin C1 exhibits other biological activities that could be beneficial for human health, as well as other fields of applications. Overall, this study, by using an in vivo infection approach, confirms the antimicrobial clinical potential and highlights the multiple functional properties of ruminococcin C1, thus extending its therapeutic interest.

scholarly journals Efficacy of a novel lantibiotic, CMB001, against MRSA

2021 ◽  
Author(s):  
Jerzy Karczewski ◽  
Christine M Brown ◽  
Yukari Maezato ◽  
Stephen P Krasucki ◽  
Stephen J Streatfield
Keyword(s):  
Antibacterial Activity ◽  
Pharmacokinetic Analysis ◽  
Maximum Tolerable Dose ◽  
In Vivo Efficacy ◽  
Clostridioides Difficile ◽  
Alternative Treatment Option ◽  
Significant Damage ◽  
Tolerable Dose

Abstract Objectives To evaluate the efficacy of a novel lantibiotic, CMB001, against MRSA biofilms in vitro and in an in vivo experimental model of bacterial infection. Methods Antibacterial activity of CMB001 was measured in vitro after its exposure to whole blood or to platelet-poor plasma. In vitro efficacy of CMB001 against a Staphylococcus aureus biofilm was studied using scanning electron microscopy. The maximum tolerable dose in mice was determined and a preliminary pharmacokinetic analysis for CMB001 was performed in mice. In vivo efficacy was evaluated in a neutropenic mouse thigh model of infection. Results CMB001 maintained its antibacterial activity in the presence of blood or plasma for up to 24 h at 37°C. CMB001 efficiently killed S. aureus within the biofilm by causing significant damage to the bacterial cell wall. The maximum tolerable dose in mice was established to be 10 mg/kg and could be increased to 30 mg/kg in mice pretreated with antihistamines. In neutropenic mice infected with MRSA, treatment with CMB001 reduced the bacterial burden with an efficacy equivalent to that of vancomycin. Conclusions CMB001 offers potential as an alternative treatment option to combat MRSA. It will be of interest to evaluate the in vivo efficacy of CMB001 against infections caused by other pathogens, including Clostridioides difficile and Acinetobacter baumannii, and to expand its pharmacokinetic/pharmacodynamic parameters and safety profile.

scholarly journals ZN148 Is a Modular Synthetic Metallo-β-Lactamase Inhibitor That Reverses Carbapenem Resistance in Gram-Negative Pathogens In Vivo

2020 ◽  
Vol 64 (6) ◽  
Author(s):  
Ørjan Samuelsen ◽  
Ove Alexander Høgmoen Åstrand ◽  
Christopher Fröhlich ◽  
Adam Heikal ◽  
Susann Skagseth ◽  
...  
Keyword(s):  
Active Site ◽  
Therapeutic Potential ◽  
Treatment Options ◽  
Carbapenem Resistance ◽  
Functional Space ◽  
Bactericidal Effect ◽  
Gram Negative ◽  
Content Type

ABSTRACT Carbapenem-resistant Gram-negative pathogens are a critical public health threat and there is an urgent need for new treatments. Carbapenemases (β-lactamases able to inactivate carbapenems) have been identified in both serine β-lactamase (SBL) and metallo-β-lactamase (MBL) families. The recent introduction of SBL carbapenemase inhibitors has provided alternative therapeutic options. Unfortunately, there are no approved inhibitors of MBL-mediated carbapenem-resistance and treatment options for infections caused by MBL-producing Gram-negatives are limited. Here, we present ZN148, a zinc-chelating MBL-inhibitor capable of restoring the bactericidal effect of meropenem and in vitro clinical susceptibility to carbapenems in >98% of a large international collection of MBL-producing clinical Enterobacterales strains (n = 234). Moreover, ZN148 was able to potentiate the effect of meropenem against NDM-1-producing Klebsiella pneumoniae in a murine neutropenic peritonitis model. ZN148 showed no inhibition of the human zinc-containing enzyme glyoxylase II at 500 μM, and no acute toxicity was observed in an in vivo mouse model with cumulative dosages up to 128 mg/kg. Biochemical analysis showed a time-dependent inhibition of MBLs by ZN148 and removal of zinc ions from the active site. Addition of exogenous zinc after ZN148 exposure only restored MBL activity by ∼30%, suggesting an irreversible mechanism of inhibition. Mass-spectrometry and molecular modeling indicated potential oxidation of the active site Cys221 residue. Overall, these results demonstrate the therapeutic potential of a ZN148-carbapenem combination against MBL-producing Gram-negative pathogens and that ZN148 is a highly promising MBL inhibitor that is capable of operating in a functional space not presently filled by any clinically approved compound.

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