Design of inhibitors of Helicobacter pylori glutamate racemase as selective antibacterial agents: Incorporation of imidazoles onto a core pyrazolopyrimidinedione scaffold to improve bioavailabilty

2012 ◽  
Vol 22 (17) ◽  
pp. 5600-5607 ◽  
Author(s):  
Gregory S. Basarab ◽  
Pamela Hill ◽  
Charles J. Eyermann ◽  
Madhu Gowravaram ◽  
Helena Käck ◽  
...  
Keyword(s):  
Helicobacter Pylori ◽  
Antibacterial Agents ◽  
Glutamate Racemase

Eradication of Helicobacter pylori: the power of nanosized formulations

Nanomedicine ◽  
2020 ◽  
Vol 15 (5) ◽  
pp. 527-542
Author(s):  
Qianyu Zhang ◽  
Wen Wu ◽  
Jinqiang Zhang ◽  
Xuefeng Xia
Keyword(s):  
Helicobacter Pylori ◽  
Antibiotic Resistance ◽  
Peptic Ulcer ◽  
Gastric Carcinoma ◽  
Antibacterial Agents ◽  
Antimicrobial Agents ◽  
Mucosal Barrier ◽  
Harsh Environment ◽  
H Pylori ◽  
Cure Rates

Helicobacter pylori is a pathogen that is considered to cause several gastric disorders such as chronic gastritis, peptic ulcer and even gastric carcinoma. The current therapeutic regimens mainly constitute of a combination of several antimicrobial agents and proton pump inhibitors. However, the prevalence of antibiotic resistance has been significantly lowering the cure rates over the years. Nanocarriers possess unique strengths in this regard owing to the fact that they can protect the drugs (such as antibiotics) from the harsh environment in the stomach, penetrate the mucosal barrier and deliver drugs to the desired site. In this review we summarized recent studies of different antibacterial agents orally delivered by nanosized carriers for the eradication of H. pylori.

Isolation of Peptide Ligands that Inhibit Glutamate Racemase Activity from a Random Phage Display Library

2000 ◽  
Vol 5 (6) ◽  
pp. 435-440 ◽  
Author(s):  
Woo-Chang Kim ◽  
Hae-Ik Rhee ◽  
Boo-Kil Park ◽  
Kyoung-Ho Suk ◽  
Sang-Hoon Cha
Keyword(s):  
Cell Wall ◽  
Phage Display ◽  
Antibacterial Agents ◽  
Bacterial Resistance ◽  
Phage Display Library ◽  
Peptide Sequence ◽  
Membrane Function ◽  
Glutamate Racemase ◽  
Positive Phage

Several new antibacterial agents are currently being developed in response to the emergence of bacterial resistance to existing antibiotic substances. The new agents include compounds that interfere with bacterial membrane function. The peptidoglycan component of the bacterial cell wall is synthesized by glutamate racemase, and this enzyme is responsible for the biosynthesis of d-glutamate, which is an essential component of cell wall peptidoglycan. In this study, we screened a phage display library expressing random dodecapeptides on the surface of bacteriophage against an Escherichia coli glutamate racemase, and isolated specific peptide sequences that bind to the enzyme. Twenty-seven positive phage clones were analyzed, and seven different peptide sequences were obtained. Among them, the peptide sequence His-Pro-Trp-His-Lys-Lys-His-Pro-Asp-Arg-Lys-Thr was found most frequently, suggesting that this peptide might have the highest affinity to glutamate racemase. The positive phage clones and HPWHKKHPDRKT synthetic peptide were able to inhibit glutamate racemase activity in vitro, implying that our peptide inhibitors may be utilized for the molecular design of new potential antibacterial agents targeting cell wall synthesis.

scholarly journals Anti-Helicobacter Pylori Activities of Natural Isopentenyloxycinnamyl Derivatives from Boronia Pinnata

2012 ◽  
Vol 7 (10) ◽  
pp. 1934578X1200701 ◽  
Author(s):  
Cécile Ribeiro da Silva ◽  
Valérie Michel ◽  
Salvatore Genovese ◽  
Marie-Christine Prévost ◽  
Francesco Epifano ◽  
...  
Keyword(s):  
Helicobacter Pylori ◽  
Antibacterial Agents ◽  
Bacterial Surface ◽  
Bacterial Cultures ◽  
Bacterial Morphology ◽  
Boropinic Acid ◽  
H Pylori ◽  
In Vivo Effects

In this study we investigated the anti- Helicobacter pylori activity of four isopentenyloxycinnamyl derivatives from the Australian shrub Boronia pinnata Sm. (Rutaceae), structurally related to boropinic acid: ( E)-3-(4-(3-methylbut-2-enyloxy)-3,5-dimethoxyphenyl)acrylaldehyde (1), boropinol C (2), boropinal (3) and boropinol A (4). In vitro growth of H. pylori strains 26695 and B128 was analyzed in liquid culture with increasing doses of these compounds. Bacterial morphology was visualized by scanning electron microscopy. The in vivo effects of the two most efficient molecules that reduced bacterial growth in vitro, compounds 3 and 4, were investigated on H. pylori gastric colonization in the mouse model. The presence of these compounds in the bacterial cultures led to alterations of bacterial surface and flagella. In vivo, both compounds 3 and 4 at 250 μM reduced significantly the ability of H. pylori to colonize the gastric mucosa of mice, compared with untreated ones. These data indicate that these natural isopentenyloxycinnamyl derivatives related to boropinic acid can be considered as novel antibacterial agents with anti- H. pylori activity.

Theoretical Analysis of the Catalytic Mechanism of Helicobacter pylori Glutamate Racemase

2012 ◽  
Vol 116 (41) ◽  
pp. 12406-12414 ◽  
Author(s):  
Edgar Mixcoha ◽  
Mireia Garcia-Viloca ◽  
José M. Lluch ◽  
Àngels González-Lafont
Keyword(s):  
Helicobacter Pylori ◽  
Theoretical Analysis ◽  
Catalytic Mechanism ◽  
Glutamate Racemase

scholarly journals Pyridodiazepine Amines Are Selective Therapeutic Agents for Helicobacter pylori by Suppressing Growth through Inhibition of Glutamate Racemase but Are Predicted To Require Continuous Elevated Levels in Plasma To Achieve Clinical Efficacy

2015 ◽  
Vol 59 (4) ◽  
pp. 2337-2342 ◽  
Author(s):  
Boudewijn L. M. de Jonge ◽  
Amy Kutschke ◽  
Joseph V. Newman ◽  
Michael T. Rooney ◽  
Wei Yang ◽  
...  
Keyword(s):  
Helicobacter Pylori ◽  
Therapeutic Agents ◽  
Infection Model ◽  
Content Type ◽  
Peptidoglycan Biosynthesis ◽  
Glutamate Racemase ◽  
Mouse Infection Model ◽  
Exposure Levels ◽  
H Pylori ◽  
Extended Exposure

ABSTRACTA pyridodiazepine amine inhibitor ofHelicobacter pyloriglutamate racemase (MurI) was characterized. The compound was selectively active againstH. pylori, and growth suppression was shown to be mediated through the inhibition of MurI by several methods. In killing kinetics experiments, the compound showed concentration-independent activity, with about a 2-log loss of viability in 24 h. A demonstration of efficacy in a mouse infection model was attempted but not achieved, and this was attributed to the failure to attain extended exposure levels above the MIC for >95% of the time. This index and magnitude were derived from pharmacokinetic-pharmacodynamic (PK-PD) studies with amoxicillin, another inhibitor of peptidoglycan biosynthesis that showed slow killing kinetics similar to those of the pyridodiazepine amines. These studies indicate that MurI and other enzymes involved in peptidoglycan biosynthesis may be less desirable targets for monotherapy directed againstH. pyloriif once-a-day dosing is required.

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