scholarly journals Inhibition of Bacterial Ribosome Assembly: a Suitable Drug Target?

2009 ◽  
Vol 73 (1) ◽  
pp. 22-35 ◽  
Author(s):  
Bruce A. Maguire
Keyword(s):  
Drug Target ◽  
Ribosome Assembly ◽  
Potential Target ◽  
Antibiotic Action ◽  
Bacterial Ribosome ◽  
New Antibiotics ◽  
The Many ◽  
In Vivo Synthesis

SUMMARY The assembly of bacterial ribosomes is viewed with increasing interest as a potential target for new antibiotics. The in vivo synthesis and assembly of ribosomes are briefly reviewed here, highlighting the many ways in which assembly can be perturbed. The process is compared with the model in vitro process from which much of our knowledge is derived. The coordinate synthesis of the ribosomal components is essential for their ordered and efficient assembly; antibiotics interfere with this coordination and therefore affect assembly. It has also been claimed that the binding of antibiotics to nascent ribosomes prevents their assembly. These two contrasting models of antibiotic action are compared and evaluated. Finally, the suitability and tractability of assembly as a drug target are assessed.

scholarly journals A tRNA-acetylating toxin and detoxifying enzyme in Mycobacterium tuberculosis.

2021 ◽  
Author(s):  
Francesca Guglielmini Tomasi ◽  
Alexander M. J. Hall ◽  
Jessica T. P. Schweber ◽  
Charles L. Dulberger ◽  
Kerry McGowen ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Drug Target ◽  
Essential Role ◽  
Fundamental Aspect ◽  
Sequencing Data ◽  
Changing Environments ◽  
New Antibiotics ◽  
Detoxifying Enzyme

Toxin-antitoxin (TA) systems allow bacteria to adapt to changing environments without altering gene expression. Despite being overrepresented in Mycobacterium tuberculosis (Mtb), their individual physiological roles remain elusive. We describe a TA system in Mtb which we have named TacAT due to its homology to previously discovered systems in Salmonella. The toxin, TacT, blocks growth by acetylating glycyl-tRNAs and inhibiting translation. Its effects are reversed by the enzyme peptidyl tRNA hydrolase (Pth), which also cleaves peptidyl tRNAs that are prematurely released from stalled ribosomes. Pth is essential in most bacteria and thereby has been proposed as a promising drug target for complex pathogens like Mtb. Transposon sequencing data suggest that the tacAT operon is nonessential for Mtb growth in vitro, and premature stop mutations in this TA system present in some clinical isolates suggest that it is also dispensable in vivo. We assessed whether TacT modulates pth essentiality in Mtb, as drugs targeting Pth might be ineffective if TacAT is disrupted. We find that pth essentiality is unaffected by the absence of tacAT. These results highlight a fundamental aspect of mycobacterial biology and indicate that Pth's essential role hinges on its peptidyl-tRNA hydrolase activity. Our work underscores Pth's potential as a viable target for new antibiotics.

Repurposing celecoxib analogues as leads for antibiotics

2021 ◽  
Author(s):  
Baowei Yang ◽  
Yicheng Mei ◽  
Qianhui Li ◽  
Mengyuan Zhang ◽  
Huiling Tang ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Enzyme Inhibition ◽  
Mild Improvement ◽  
New Antibiotics ◽  
Cytotoxicity Assessment ◽  
Improvement In Survival ◽  
In Vivo Cytotoxicity ◽  
Further Development

There is an urgent need for new antibiotics and alternative strategies to combat bacterial pathogens. Molecular docking, antibacterial evaluation in vitro and in vivo, cytotoxicity assessment and enzyme inhibition analyses were performed. Compound 12 exhibited antimicrobial activity against Staphylococcus aureus (MIC: 4 μg/ml), various clinically isolated strains of MRSA (MIC: 4–16 μg/ml) and Acinetobacter baumannii (MIC: 4 μg/ml) when combined with subinhibitory concentrations of colistin B. Compound 12 (20 mg/kg) yielded mild improvement in survival of methicillin-resistant Staphylococcus aureus (MRSA)-infected mice. Additionally, enzyme inhibition tests showed that compound 12 exhibited inhibitory effects against S. aureus dihydrofolate reductase (105.1 μg/ml) and DNA gyrase (122.8 μg/ml). Compound 12 is a promising antibacterial candidate for further development.

scholarly journals A causal role for TRESK loss of function in migraine mechanisms

Brain ◽  
2019 ◽  
Vol 142 (12) ◽  
pp. 3852-3867 ◽  
Author(s):  
Philippa Pettingill ◽  
Greg A Weir ◽  
Tina Wei ◽  
Yukyee Wu ◽  
Grace Flower ◽  
...  
Keyword(s):  
Potassium Channel ◽  
Drug Target ◽  
Causal Role ◽  
Potential Drug Target ◽  
Potential Drug ◽  
Loss Of Function

The two-pore potassium channel TRESK is a potential drug target in pain and migraine. Pettingill et al. show that the F139WfsX2 mutation causes TRESK loss of function and hyperexcitability in nociceptors derived from iPSCs of patients with migraine. Cloxyquin, a TRESK activator, reverses migraine-relevant phenotypes in vitro and in vivo.

scholarly journals Dopamine receptor D1- and D2-agonists do not spark brown adipose tissue thermogenesis in mice

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Francesca-Maria Raffaelli ◽  
Julia Resch ◽  
Rebecca Oelkrug ◽  
K. Alexander Iwen ◽  
Jens Mittag
Keyword(s):  
Adipose Tissue ◽  
Brown Adipose Tissue ◽  
Dopamine Receptor ◽  
Ex Vivo ◽  
Potential Target ◽  
D2 Agonist ◽  
Obesity And Diabetes ◽  
Brown Adipose

AbstractBrown adipose tissue (BAT) thermogenesis is considered a potential target for treatment of obesity and diabetes. In vitro data suggest dopamine receptor signaling as a promising approach; however, the biological relevance of dopamine receptors in the direct activation of BAT thermogenesis in vivo remains unclear. We investigated BAT thermogenesis in vivo in mice using peripheral administration of D1-agonist SKF38393 or D2-agonist Sumanirole, infrared thermography, and in-depth molecular analyses of potential target tissues; and ex vivo in BAT explants to identify direct effects on key thermogenic markers. Acute in vivo treatment with the D1- or D2-agonist caused a short spike or brief decrease in BAT temperature, respectively. However, repeated daily administration did not induce lasting effects on BAT thermogenesis. Likewise, neither agonist directly affected Ucp1 or Dio2 mRNA expression in BAT explants. Taken together, the investigated agonists do not seem to exert lasting and physiologically relevant effects on BAT thermogenesis after peripheral administration, demonstrating that D1- and D2-receptors in iBAT are unlikely to constitute targets for obesity treatment via BAT activation.

scholarly journals Trifluoromethionine, a Prodrug Designed against Methionine γ-Lyase-Containing Pathogens, Has Efficacy In Vitro and In Vivo against Trichomonas vaginalis

2001 ◽  
Vol 45 (6) ◽  
pp. 1743-1745 ◽  
Author(s):  
Graham H. Coombs ◽  
Jeremy C. Mottram
Keyword(s):  
Drug Target ◽  
Trichomonas Vaginalis ◽  
Anaerobic Bacteria ◽  
Protozoan Parasite ◽  
Chemotherapeutic Agents ◽  
Single Step ◽  
Lesion Formation ◽  
Highly Active

ABSTRACT Methionine γ-lyase, the enzyme which catalyzes the single-step conversion of methionine to α-ketobutyrate, ammonia, and methanethiol, is highly active in many anaerobic pathogenic microorganisms but has no counterpart in mammals. This study tested the hypothesis that this pathogen-specific enzyme can be exploited as a drug target by prodrugs that are exclusively activated by it. Trifluoromethionine was confirmed as such a prodrug and shown to be highly toxic in vitro to the anaerobic protozoan parasiteTrichomonas vaginalis, to anaerobic bacteria containing methionine γ-lyase, and to Escherichia coli expressing the trichomonad gene. The compound also has exceptional activity against the parasite growing in vivo, with a single dose preventing lesion formation in five of the six mice challenged. These findings suggest that trifluoromethionine represents a lead compound for a novel class of anti-infective drugs with potential as chemotherapeutic agents against a range of prokaryotic and eukaryotic anaerobic pathogens.

The Indispensable Value of Clinical Trials in the Modernization of Traditional Chinese Medicine: 12 Years' Experience at CUHK and Future Perspectives

2014 ◽  
Vol 42 (03) ◽  
pp. 587-604 ◽  
Author(s):  
Willmann Liang ◽  
David T. Yew ◽  
Kam Lun Hon ◽  
Chun Kwok Wong ◽  
Timothy C. Y. Kwok ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Chinese Medicine ◽  
Herbal Medicines ◽  
Chinese Herbs ◽  
Protective Effects ◽  
Beneficial Effects ◽  
Artery Disease ◽  
The Many

The last decade has seen a wealth of information reporting the beneficial effects of Chinese herbal medicines. While a lot more studies were done using in vitro and in vivo research platforms, much fewer investigations were conducted according to evidence-based requirements in clinical settings. The Institute of Chinese Medicine at the Chinese University of Hong Kong (CUHK) has had the opportunity to collaborate with clinicians over the years to initiate and conduct dozens of clinical trials investigating and verifying the therapeutic values of Chinese herbs in selected disease conditions. Of the many disorders, we chose to focus on those that are known for their difficulties achieving perfect results with conventional treatment methods. Examples include non-healing ulcers, allergic conditions, degenerative diseases and cancer. Protective effects of the herbs in such chronic diseases as coronary artery disease and osteoporosis were also part of our focus. Even in healthy individuals and those recovering from chemotherapy, Chinese herbs could help with the immune system and were studied in our clinical trials as well. This paper aims to highlight the important findings from these clinical studies while at the same time, stressing the indispensable value of clinical trials in modernizing the use of Chinese herbs in present-day medicine.

Measurement of the absolute synthesis of soluble and insoluble elastin by chick aortic tissue

1983 ◽  
Vol 61 (10) ◽  
pp. 1079-1084 ◽  
Author(s):  
Fred W. Keeley ◽  
Dorothy J. Johnson
Keyword(s):  
Significant Proportion ◽  
State Level ◽  
Aortic Tissue ◽  
In Vitro Synthesis ◽  
Stage Of Development ◽  
Absolute Synthesis ◽  
Rate Of Accumulation ◽  
In Vivo Synthesis

The rate of in vitro synthesis of soluble and insoluble elastin by thoracic aorta of 2-day-old chicks has been measured in absolute terms. In the absence of β-aminopropionitrile (βAPN), the steady state level of soluble elastin was 120 pmol/100 mg of aortic tissue or 3.7 μg/whole aorta segment. The rate of synthesis of elastin in vitro was approximately 130 μg/day per whole aorta segment. This is three- to four-fold lower than the estimated rate of in vivo synthesis for a comparable segment of aortic tissue at the same stage of development. Pulse-chase experiments suggested that this difference was not due to in vitro proteolysis of a significant proportion of the newly synthesized soluble elastin, but rather that the conversion of soluble to insoluble elastin was both rapid and efficient. These experiments also indicated the presence in aortic tissue of a substantial pool of elastin of intermediate solubility. Although inclusion of βAPN in the incubation medium resulted in an increase in the amount of soluble elastin in aortic tissue, the rate of accumulation of newly synthesized soluble elastin in the presence of this inhibitor of cross-linking was not linear, but decreased with incubation time. Furthermore, although βAPN effectively suppressed the appearance of insoluble elastin for at least 2 h, some escape from the effect of this inhibitor was seen with further incubation. In general, βAPN significantly depressed elastin synthesis.

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