Nagstatin, a new inhibitor of N-acetyl-.BETA.-D-glucosaminidase, produced by Streptomyces amakusaensis MG846-fF3. Taxonomy, production, isolation, physico-chemical properties and biological activities.

Aoyagi, Takaaki; Suda, Hiroyuki; Uotani, Kazumichi; Kojima, Fukiko; Aoyama, Takayuki; Horiguchi, Kayo; Hamada, Masa; Takeuchi, Tomio

doi:10.7164/antibiotics.45.1404

Cited by 110 publications

(47 citation statements)

References 10 publications

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“…Few inhibitors of NagZ are known, and those that are known bear geometric resemblance to this proposed oxocarbenium ion-like transition state (37,50). Two of the most potent inhibitors of glycosidases for several families of enzymes are the tetrahydroimidazopyridines and the 2-acetamido-glucopyranosyl hydroximolactones (51 (54), and a related analogue gluco-nagstatin (58) (Fig. 2) have been shown to potently inhibit the family 84 human O-GlcNAcase (55,56) and the family 20 human ␤-hexosaminidases (52, 54, 57-61).…”

Section: Resultsmentioning

confidence: 99%

Small Molecule Inhibitors of a Glycoside Hydrolase Attenuate Inducible AmpC-mediated β-Lactam Resistance

Stubbs

Balcewich

Mark

et al. 2007

Journal of Biological Chemistry

106

145

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The increasing spread of plasmid-borne ampC-ampR operons is of considerable medical importance, since the AmpC ␤-lactamases they encode confer high level resistance to many third generation cephalosporins. Induction of AmpC ␤-lactamase from endogenous or plasmid-borne ampC-ampR operons is mediated by a catabolic inducer molecule, 1,6-anhydro-Nacetylmuramic acid (MurNAc) tripeptide, an intermediate of the cell wall recycling pathway derived from the peptidoglycan. Here we describe a strategy for attenuating the antibiotic resistance associated with the ampC-ampR operon by blocking the formation of the inducer molecule using small molecule inhibitors of NagZ, the glycoside hydrolase catalyzing the formation of this inducer molecule. The structure of the NagZ-inhibitor complex provides insight into the molecular basis for inhibition and enables the development of inhibitors with 100-fold selectivity for NagZ over functionally related human enzymes. These PUGNAc-derived inhibitors reduce the minimal inhibitory concentration (MIC) values for several clinically relevant cephalosporins in both wild-type and AmpC-hyperproducing strains lacking functional AmpD.The expression of inducible chromosomal AmpC ␤-lactamases (1, 2) is one increasingly problematic resistance mechanism seen in many Gram-negative bacteria, including clinically opportunistic pathogens, such as Pseudomonas aeruginosa and Citrobacter freundii. These AmpC ␤-lactamases inactivate a broad range of ␤-lactam antibiotics, thereby conferring resistance to clinically important cephamycins, cephalosporins, and even monobactams, next generation ␤-lactams designed to be stable against ␤-lactamases (3). One alarming development resulting from continued ␤-lactam use is the spread of genetically diverse, plasmid-borne ampC, including those that are under inducible control. Indeed, the movement of ampC genes onto plasmids (4 -8) as well as other transposable elements has greatly increased the prevalence of this type of resistance mechanism in Gram-negative organisms (9). The regulation of ampC gene expression can vary between genera of Gram-negative bacteria. In some, chromosomal ampC is expressed constitutively, although high level expression has been suggested to decrease bacterial fitness and virulence, at least in Salmonella enterica (10). Often, however, chromosomal ampC ␤-lactamase is inducible as found in various clinically relevant opportunistic pathogens, such as Enterobacter spp., and P. aeruginosa (11,12).A major achievement in the field of antibiotic research has been the discovery of ␤-lactamase inhibitors. These inhibitors have been shown, in some cases, to reverse antibiotic resistance mediated by certain classes of ␤-lactamase. There are currently three main ␤-lactamase inhibitors available on the market, each having the same ␤-lactam core found in ␤-lactam antibiotics. One of these inhibitors, clavulanic acid, however has been found to be of limited use against AmpC (13, 14). The other two, sulbactam and tazobactam, demonstrate effectiveness against...

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Section: Resultsmentioning

confidence: 99%

Small Molecule Inhibitors of a Glycoside Hydrolase Attenuate Inducible AmpC-mediated β-Lactam Resistance

Stubbs

Balcewich

Mark

et al. 2007

Journal of Biological Chemistry

106

145

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“…We wanted to know if the relationship between the inhibitory activity of esters and acids is also valid for the inhibition of the N-acetyl-b-glucosaminidase from bovine kidney 1 ) by the N-acetylglucosamine-derived imidazole-2-acetate 14 and the corresponding acid 15. These compounds will also allow testing the effect of the galacto-vs. gluco-configuration on the inhibition.…”

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confidence: 99%

Synthesis of N‐Acetylglucosamine‐Derived Nagstatin Analogues and Their Evaluation as Glycosidase Inhibitors

Terinek¹,

Vasella²

2005

Helvetica Chimica Acta

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The gluco-configured analogue 15 of nagstatin (1) and the methyl ester 14 were synthesized via condensation of the thionolactams 17 or 18 with the b-amino ester 19. The silyl ethers 20 and 21 resulting from 17 were desilylated to 22 and 23; these alcohols were directly obtained by condensing 18 and 19. The attempted substitution of the C(8)ÀOH group of 22 by azide under Mitsunobu conditions led unexpectedly to the deoxygenated a-azido esters 24. The desired azide 25 was obtained by treating the manno-configured alcohol 23 with diphenyl phosphorazidate. The azide was transformed to the debenzylated acetamido ester 14 that was hydrolyzed to the nagstatin analogue 15. The imidazole-2-acetates 14 and 15 are nanomolar inhibitors of the Nacetyl-b-glucosaminidases from Jack beans and from bovine kidney, submicromolar to micromolar inhibitors of the b-glucosidase from Caldocellum saccharolyticum, and rather weak inhibitors of the snail b-mannosidase. In all cases, the ester was a stronger inhibitor than the corresponding acid. As expected from their glucoconfiguration, both imidazopyridines 14 and 15 are stronger inhibitors of the b-N-acetylglucosaminidase from bovine kidney than nagstatin.Introduction. ± Nagstatin (1), a strong inhibitor of several hexosaminidases [1 ± 4], is a N-acetylgalactosamine-derived tetrahydropyridoimidazole-2-acetic acid [5]. Its inhibitory activity is essentially associated with the imidazole ring and not with the carboxymethyl substituent [2], although substituents on the imidazole ring may strongly affect the inhibition of b (and a-)-glycosidases [6 ± 8]. In the preceding paper [9], we described the influence of the hydrophobic character of C(2)-methyl ester and carboxylic acid substituents on the inhibition of b-glycosidases. Imidazole-2-propionates 10 ± 13 are stronger inhibitors of the b-glucosidase from Caldocellum saccharolyticum and of the b-mannosidase from snail than imidazole-2-acetates 6 ± 9, and these are stronger than imidazole-2-carboxylates 2 ± 5. There is a parallel sequence of inhibitory activity for the methyl esters and the corresponding acids, with the esters being stronger inhibitors.

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“…Currently known highly efficient inhibitors, with K i values in the nm range, include 1,2-dideoxy-2'-methyl-a-d-glucopyranoso-[2,1-d]-D2'-thiazoline (NGT), [13] N-acetylglucosaminono-1,5-lactone O-(phenylcarbamoyl)oxime (PUGNAc), [14] and nagstatin. [15] However, these inhibitors are not specific, because their targets cover most of the known GH20 b-N-acetyl-d-hexosaminidases.…”

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confidence: 99%

Synthesis, Evaluation, and Mechanism of N,N,N‐Trimethyl‐D‐glucosamine‐(1→4)‐chitooligosaccharides as Selective Inhibitors of Glycosyl Hydrolase Family 20 β‐N‐Acetyl‐D‐hexosaminidases

et al. 2010

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GH20 β-N-acetyl-D-hexosaminidases are enzymes involved in many vital processes. Inhibitors that specifically target GH20 enzymes in pests are of agricultural and economic importance. Structural comparison has revealed that the bacterial chitindegrading β-N-acetyl-D-hexosaminidases each have an extra +1 subsite in the active site; this structural difference could be exploited for the development of selective inhibitors. N,N,Ntrimethyl-D-glucosamine (TMG)-chitotriomycin, which contains three GlcNAc residues, is a natural selective inhibitor against bacterial and insect β-N-acetyl-D-hexosaminidases. However, our structural alignment analysis indicated that the two GlcNAc residues at the reducing end might be unnecessary. To prove this hypothesis, we designed and synthesized a series of TMG-chitotriomycin analogues containing one to four GlcNAc units. Inhibitory kinetics and molecular docking showed that TMG-(GlcNAc)(2), is as active as TMG-chitotriomycin [TMG-(GlcNAc)(3)]. The selective inhibition mechanism of TMG-chitotriomycin was also explained.

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Nagstatin, a new inhibitor of N-acetyl-.BETA.-D-glucosaminidase, produced by Streptomyces amakusaensis MG846-fF3. Taxonomy, production, isolation, physico-chemical properties and biological activities.

Cited by 110 publications

References 10 publications

Small Molecule Inhibitors of a Glycoside Hydrolase Attenuate Inducible AmpC-mediated β-Lactam Resistance

Small Molecule Inhibitors of a Glycoside Hydrolase Attenuate Inducible AmpC-mediated β-Lactam Resistance

Synthesis of N‐Acetylglucosamine‐Derived Nagstatin Analogues and Their Evaluation as Glycosidase Inhibitors

Synthesis, Evaluation, and Mechanism of N,N,N‐Trimethyl‐D‐glucosamine‐(1→4)‐chitooligosaccharides as Selective Inhibitors of Glycosyl Hydrolase Family 20 β‐N‐Acetyl‐D‐hexosaminidases

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