NUDT18 catalyzes hydrolysis of active metabolites of the antivirals Remdesivir and Ribavirin

Remdesivir (GS-5734) has gained considerable interest due to its activity against replication of SARS-CoV2. Remdesivir is a broad-spectrum antiviral prodrug that is hydrolyzed intracellularly and phosphorylated by cellular kinases to its active triphosphate form (Remdesivir-TP). Here we tested Remdesivir-TP as a substrate for a panel of human hydrolases and found that NUDIX hydrolase 18 (NUDT18) catalyzes the hydrolysis of Remdesivir-TP. NUDT18 is expressed in respiratory epithelial cells suggesting that NUDT18 may limit the antiviral efficacy of Remdesivir by decreasing the intracellular concentration of its active metabolite at its intended site of action. The kcat of NUDT18 for Remdesivir-TP was determined to 2.6 s-1 and the Km value was 156 μM, suggesting that NUDT18 catalyzed hydrolysis occurs in cells. In addition, we found that the triphosphate of the antiviral Ribavirin, with broad-spectrum activity against several RNA and DNA viruses, was hydrolyzed by NUDT18, albeit with a lower efficiency compared to Remdesivir-TP. NUDT18 activity was also tested with the triphosphates of the antivirals Sofosbuvir and Aciclovir for which low activity, in comparison to activities with Remdesivir-TP and Ribavirin-TP, was detected. These results suggest that NUDT18 can act as a cellular sanitizer and may influence the antiviral efficacy of Remdesivir and Ribavirin.

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NB2001, a Novel Antibacterial Agent with Broad-Spectrum Activity and Enhanced Potency against β-Lactamase-Producing Strains

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.46.5.1262-1268.2002 ◽

2002 ◽

Vol 46 (5) ◽

pp. 1262-1268 ◽

Cited By ~ 28

Author(s):

Qing Li ◽

Jean Y. Lee ◽

Rosario Castillo ◽

Mark S. Hixon ◽

Catherine Pujol ◽

...

Keyword(s):

Broad Spectrum ◽

Antibacterial Agent ◽

Bacterial Resistance ◽

Enterobacter Aerogenes ◽

Order Rate Constant ◽

Common Mechanism ◽

E Coli ◽

Lactam Ring ◽

Spectrum Activity ◽

Hydrolysis Of

ABSTRACT Enzyme-catalyzed therapeutic activation (ECTA) is a novel prodrug strategy to overcome drug resistance resulting from enzyme overexpression. β-Lactamase overexpression is a common mechanism of bacterial resistance to β-lactam antibiotics. We present here the results for one of the β-lactamase ECTA compounds, NB2001, which consists of the antibacterial agent triclosan in a prodrug form with a cephalosporin scaffold. Unlike conventional β-lactam antibiotics, where hydrolysis of the β-lactam ring inactivates the antibiotic, hydrolysis of NB2001 by β-lactamase releases triclosan. Evidence supporting the proposed mechanism is as follows. (i) NB2001 is a substrate for TEM-1 β-lactamase, forming triclosan with a second-order rate constant (k cat/Km ) of greater than 77,000 M−1 s−1. (ii) Triclosan is detected in NB2001-treated, β-lactamase-producing Escherichia coli but not in E. coli that does not express β-lactamase. (iii) NB2001 activity against β-lactamase-producing E. coli is decreased in the presence of the β-lactamase inhibitor clavulanic acid. NB2001 was similar to or more potent than reference antibiotics against clinical isolates of Staphylococcus aureus (including MRSA), Staphylococcus epidermidis, Streptococcus pneumoniae, vancomycin-resistant Enterococcus faecalis, Moraxella catarrhalis and Haemophilus influenzae. NB2001 is also active against Klebsiella pneumoniae, Enterobacter aerogenes, and Enterobacter cloacae. The results indicate that NB2001 is a potent, broad-spectrum antibacterial agent and demonstrate the potential of ECTA in overcoming β-lactamase-mediated resistance.

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CoMFA study of distamycin analogs binding to the minor-groove of DNA: a unified model for broad-spectrum activity

Journal of Molecular Modeling ◽

10.1007/s00894-007-0234-3 ◽

2007 ◽

Vol 13 (10) ◽

pp. 1099-1108 ◽

Cited By ~ 1

Author(s):

Santosh A. Khedkar ◽

Alpeshkumar K. Malde ◽

Evans C. Coutinho

Keyword(s):

Broad Spectrum ◽

Minor Groove ◽

Unified Model ◽

Spectrum Activity ◽

Comfa Study ◽

Broad Spectrum Activity

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Five-Year Longitudinal Assessment (2008 to 2012) of E-101 Solution Activity against Clinical Target and Antimicrobial-Resistant Pathogens

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.03020-14 ◽

2014 ◽

Vol 58 (8) ◽

pp. 4911-4914 ◽

Cited By ~ 2

Author(s):

Gerald A. Denys ◽

Chris M. Pillar ◽

Daniel F. Sahm ◽

Peter O'Hanley ◽

Jackson T. Stephens

Keyword(s):

Broad Spectrum ◽

Susceptibility Testing ◽

Bacterial Species ◽

Clinical Isolates ◽

Longitudinal Assessment ◽

Gram Negative ◽

Spectrum Activity ◽

Eskape Pathogens ◽

Negative Target ◽

Broad Spectrum Activity

ABSTRACTThis study summarizes the topical E-101 solution susceptibility testing results for 760 Gram-positive and Gram-negative target pathogens collected from 75 U.S. sites between 2008 and 2012 and 103 ESKAPE pathogens. E-101 solution maintained potent activity against all bacterial species studied for each year tested, with MICs ranging from <0.008 to 0.25 μg porcine myeloperoxidase (pMPO)/ml. These results confirm that E-101 solution retains its potent broad-spectrum activity against U.S. clinical isolates and organisms with challenging resistance phenotypes.

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A Degradation Product from Hydrolysate of Imipenem with Imis Broad-Spectrum Inhibits Metallo-β-Lactamases

Jundishapur Journal of Microbiology ◽

10.5812/jjm.108141 ◽

2020 ◽

Vol 13 (10) ◽

Author(s):

Ying Ge ◽

Li-Wei Xu ◽

Jian-Bin Zhen ◽

Cheng Chen ◽

Miao Lv ◽

...

Keyword(s):

Broad Spectrum ◽

Degradation Product ◽

Substrate Inhibition ◽

Resistant Bacteria ◽

Drug Resistant ◽

Antibiotic Resistant Bacteria ◽

Antibiotic Resistant ◽

Leaving Group ◽

Ic50 Values ◽

Hydrolysis Of

Background: Infections caused by metallo-β-lactamases (MβLs)-producing antibiotic-resistant bacteria pose a severe threat to public health. The synergistic use of current antibiotics in combination with MβL inhibitors is a promising therapeutic mode against these antibiotic-resistant bacteria. Objectives: The study aimed to probe the inhibition of MβLs and obtain the active component, P1, in the degradation product after imipenem was hydrolyzed by ImiS. Methods: The hydrolysis of two carbapenems with MβL ImiS was monitored by UV-Vis in real-time, and the degradation product from the leaving group produced after imipenem was hydrolyzed (but not for faropenem) was purified by HPLC to give one component, P1. Results: Kinetic assays revealed that P1 exhibited a broad-spectrum inhibition against VIM-2, NDM-1, ImiS, and L1, from three sub-classes of MβLs, with IC50 values of 8 - 32, 13.8 - 29.3, and 14.2 - 19.2 µM, using imipenem, cefazolin, and nitrocefin as substrates, respectively. Also, P1 showed synergistic antibacterial efficacy against drug-resistant Escherichia coli producing VIM-2, NDM-1, ImiS, and L1, in combination with antibiotics, restoring 16 to 32-fold and 32 to 128-fold efficacies of imipenem and cefazolin, respectively. Spectroscopic and Ellman's reagent analyses suggested that P1, a mercaptoethyl-form imidamide, is a mechanism-based inhibitor, while faropenem has no substrate inhibition, due to the lack of a leaving group. Conclusions: This work reveals that the hydrolysate of imipenem, a carbapenem with a good leaving group, can be used in screening for broad-spectrum inhibitors of MβLs.

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Efficacy of some medicated soaps and hand washes available in market

International Journal of Science and Research Archive ◽

10.30574/ijsra.2021.3.1.0098 ◽

2021 ◽

Vol 3 (1) ◽

pp. 047-055

Author(s):

Pimpliskar Mukesh ◽

SoumyaGounder ◽

Rahul Jadhav

Keyword(s):

Broad Spectrum ◽

Life Forms ◽

Small Scale ◽

Gram Positive ◽

Consistent Finding ◽

Gram Negative ◽

Cross Transmission ◽

Spectrum Activity ◽

Significant Measure ◽

Broad Spectrum Activity

Background: Handwashing is underlined as the absolute most significant measure to forestall cross-transmission of small-scale life forms and consequently to forestall nosocomial contaminations. Be that as it may, under routine emergency clinic practice consistent with this measure is still unsatisfactorily low, under half in many investigations distributed in the previous 20 years. This consistent finding is stressing because ongoing investigations have demonstrated that this degree of consistency won't decrease the danger of transmission of multi- medicate safe microscopic organisms in the emergency clinics. Results: In the present investigation effect of marketed hand washed namely Lifebuoy, Dettol and Savlon were tested on bacteria E. coli, S.aureus, S.pyogen, Klebshiella and, fungi Candida albicans. All the handwash at concentrated level found to be effective but only Dettol hand wash could give inhibitory action at 25ug/ml against Klebshiella while others at50ug/ml. Conclusions: Soapex and Dettol soap had broad spectrum activity as it inhibited the growth of Gram positive (Streptococcus pyogen) and Gram-negative (Escherichia coli). Liquid handwash such as Lifebuoy,Dettol and Savlon showed broad spectrum activity on both Gram-positive and Gram negative test microorganisms.

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Correction: Novel broad-spectrum activity-based probes to profile malarial cysteine proteases

PLoS ONE ◽

10.1371/journal.pone.0231231 ◽

2020 ◽

Vol 15 (3) ◽

pp. e0231231

Author(s):

Michele S. Y. Tan ◽

Dara Davison ◽

Mateo I. Sanchez ◽

Bethany M. Anderson ◽

Stephen Howell ◽

...

Keyword(s):

Broad Spectrum ◽

Cysteine Proteases ◽

Spectrum Activity ◽

Broad Spectrum Activity

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Rational design, synthesis and testing of novel tricyclic topoisomerase inhibitors for the treatment of bacterial infections part 2

RSC Medicinal Chemistry ◽

10.1039/d0md00175a ◽

2020 ◽

Vol 11 (12) ◽

pp. 1379-1385

Author(s):

R. Kirk ◽

A. Ratcliffe ◽

G. Noonan ◽

M. Uosis-Martin ◽

D. Lyth ◽

...

Keyword(s):

Broad Spectrum ◽

Bacterial Infections ◽

Rational Design ◽

Topoisomerase Ii ◽

Topoisomerase Inhibitors ◽

Design Synthesis ◽

Pharmacokinetic Properties ◽

Spectrum Activity ◽

Broad Spectrum Activity

We disclose the discovery of REDX07965, a novel tricyclic topoisomerase inhibitor (NTTI) which has broad spectrum activity, favourable in vitro pharmacokinetic properties and selectivity versus human topoisomerase II.

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ADP-ribosyltransferase in isolated nuclei from sea-urchin embryos

Biochemical Journal ◽

10.1042/bj2250429 ◽

1985 ◽

Vol 225 (2) ◽

pp. 429-434 ◽

Cited By ~ 8

Author(s):

A Isoai ◽

I Yasumasu

Keyword(s):

Sea Urchin ◽

Insoluble Fraction ◽

Cell Stage ◽

Isolated Nuclei ◽

Sea Urchin Embryos ◽

Snake Venom Phosphodiesterase ◽

Km Value ◽

Insoluble Product ◽

Adp Ribosyltransferase ◽

Hydrolysis Of

The activity of ADP-ribosyltransferase in nuclei isolated from sea-urchin embryos was estimated by the incorporation of [adenosine-14C]NAD+ into the acid-insoluble fraction. Hydrolysis of this acid-insoluble product by snake venom phosphodiesterase yielded radioactive 5′-AMP and phosphoribosyl-AMP. The incorporation of [14C]-NAD+ was inhibited by 3-aminobenzamide and nicotinamide, potent inhibitors of ADP-ribosyltransferase. [14C]NAD+ incorporation into the acid-insoluble fraction results from the reaction of ADP-ribosyltransferase. The optimum pH for the enzyme in isolated nuclei was 7.5. The enzyme, in 50 mM-Tris/HCl buffer, pH 7.5, containing 0.5 mM-NAD+ and 0.5 mM-dithiothreitol, exhibited the highest activity at 18 degrees C in the presence of 14 mM-MgCl2. The apparent Km value for NAD+ was 25 microM. The activity of the enzyme was measured in nuclei isolated from the embryos at several stages during early development. The activity was maximum at the 16-32-cell stage and then decreased to a minimum at the mesenchyme blastula stage. Thereafter its activity slightly increased at the onset of gastrulation and decreased again at the prism stage.

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Partial purification and properties of a β-N-acetylglucosaminidase from the fungus Sclerotinia fructigena

Biochemical Journal ◽

10.1042/bj1310381 ◽

1973 ◽

Vol 131 (2) ◽

pp. 381-388 ◽

Cited By ~ 59

Author(s):

F. Reyes ◽

R. J. W. Byrde

Keyword(s):

Nitrogen Source ◽

Cellulose Acetate ◽

Isoelectric Focusing ◽

Culture Filtrate ◽

Gel Filtration ◽

Partial Purification ◽

Conflicting Evidence ◽

Purification And Properties ◽

Km Value ◽

Hydrolysis Of

1. As cultures of the fungus Sclerotinia fructigena autolysed, the filtrates contained increasing quantities of a β-N-acetylglucosaminidase. 2. The enzyme was purified up to 42-fold by a combination of isoelectric focusing and gel filtration. 3. It ran as a single band in cellulose acetate strip electrophoresis and in isoelectric focusing (pI3.76). 4. The enzyme did not readily hydrolyse chitin or a glycopeptide with terminal N-acetylglucosamine residues, but rapidly degraded the N-acetylglucosamine dimer NN′-diacetylchitobiose; the monomer was readily utilized by the fungus as a nitrogen source. The Km value for hydrolysis of p-nitrophenyl β-2-acetamido-2-deoxy-d-glucopyranoside at 37°C was 2.0mm. The Sclerotinia enzyme was generally less susceptible to inhibition by 2-acetamido-2-deoxygluconolactone and other related sugars than the corresponding enzyme from other sources. Inhibition by excess of substrate was observed. 5. The culture filtrate also contained N-acetylgalactosaminidase activity; conflicting evidence was obtained as to whether the same enzyme was responsible for both hexosaminidase activities.

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