Literature summary for 3.4.21.89 extracted from

Yeh, C.H.; Walsh, S.I.; Craney, A.; Tabor, M.G.; Voica, A.F.; Adhikary, R.; Morris, S.E.; Romesberg, F.E.
Optimization of a beta-lactam scaffold for antibacterial activity via the inhibition of bacterial type I signal peptidase (2018), ACS Med. Chem. Lett., 9, 376-380 .

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Application

Application	Comment	Organism
drug development	bacterial signal peptidase I (SPase) is a target for development of beta-lactam anti-bacterial inhibitors	Staphylococcus epidermidis
drug development	bacterial signal peptidase I (SPase) is a target for development of beta-lactam anti-bacterial inhibitors	Yersinia pestis
drug development	bacterial signal peptidase I (SPase) is a target for development of beta-lactam anti-bacterial inhibitors	Escherichia coli

Inhibitors

Inhibitors	Comment	Organism
(5S,6S)-3-[(2-aminoethyl)sulfanyl]-6-[(1R)-1-hydroxyethyl]-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid	IC50 is 0.00063 mg/l	Escherichia coli
(5S,6S)-3-[(2-aminoethyl)sulfanyl]-6-[(1R)-1-hydroxyethyl]-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid	-	Staphylococcus epidermidis
(5S,6S)-3-[(2-aminoethyl)sulfanyl]-6-[(1R)-1-hydroxyethyl]-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid	-	Yersinia pestis
(5S,6S)-3-[[2-(carbamoyloxy)ethyl]sulfanyl]-6-[(1R)-1-hydroxyethyl]-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid	IC50 is 0.00096 mg/l	Escherichia coli
(5S,6S)-3-[[2-(carbamoyloxy)ethyl]sulfanyl]-6-[(1R)-1-hydroxyethyl]-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid	-	Staphylococcus epidermidis
(5S,6S)-3-[[2-(carbamoyloxy)ethyl]sulfanyl]-6-[(1R)-1-hydroxyethyl]-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid	-	Yersinia pestis
(5S,6S)-3-[[2-(dimethylamino)ethyl]sulfanyl]-6-[(1R)-1-hydroxyethyl]-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid	IC50 is 0.00395 mg/l	Escherichia coli
(5S,6S)-3-[[2-(dimethylamino)ethyl]sulfanyl]-6-[(1R)-1-hydroxyethyl]-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid	-	Staphylococcus epidermidis
(5S,6S)-3-[[2-(dimethylamino)ethyl]sulfanyl]-6-[(1R)-1-hydroxyethyl]-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid	-	Yersinia pestis
(5S,6S)-3-[[3-(dimethylcarbamoyl)cyclopentyl]sulfanyl]-6-[(1R)-1-hydroxyethyl]-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid	IC50 is 0.00122 mg/l	Escherichia coli
(5S,6S)-3-[[3-(dimethylcarbamoyl)cyclopentyl]sulfanyl]-6-[(1R)-1-hydroxyethyl]-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid	-	Staphylococcus epidermidis
(5S,6S)-3-[[3-(dimethylcarbamoyl)cyclopentyl]sulfanyl]-6-[(1R)-1-hydroxyethyl]-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid	-	Yersinia pestis
(5S,6S)-6-[(1R)-1-hydroxyethyl]-3-([2-[(iminomethyl)amino]ethyl]sulfanyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid	IC50 is 0.00104 mg/l	Escherichia coli
(5S,6S)-6-[(1R)-1-hydroxyethyl]-3-([2-[(iminomethyl)amino]ethyl]sulfanyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid	-	Staphylococcus epidermidis
(5S,6S)-6-[(1R)-1-hydroxyethyl]-3-([2-[(iminomethyl)amino]ethyl]sulfanyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid	-	Yersinia pestis
(5S,6S)-6-[(1R)-1-hydroxyethyl]-3-[(2-hydroxyethyl)sulfanyl]-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid	IC50 is 0.00149 mg/l	Escherichia coli
(5S,6S)-6-[(1R)-1-hydroxyethyl]-3-[(2-hydroxyethyl)sulfanyl]-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid	-	Staphylococcus epidermidis
(5S,6S)-6-[(1R)-1-hydroxyethyl]-3-[(2-hydroxyethyl)sulfanyl]-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid	-	Yersinia pestis
(5S,6S)-6-[(1R)-1-hydroxyethyl]-3-[[2-(methylamino)ethyl]sulfanyl]-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid	IC50 is 0.00637 mg/l	Escherichia coli
(5S,6S)-6-[(1R)-1-hydroxyethyl]-3-[[2-(methylamino)ethyl]sulfanyl]-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid	-	Staphylococcus epidermidis
(5S,6S)-6-[(1R)-1-hydroxyethyl]-3-[[2-(methylamino)ethyl]sulfanyl]-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid	-	Yersinia pestis
(5S,6S)-6-[(1R)-1-hydroxyethyl]-7-oxo-3-[[(1R)-3-oxocyclopentyl]sulfanyl]-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid	IC50 is 0.00116 mg/l	Escherichia coli
(5S,6S)-6-[(1R)-1-hydroxyethyl]-7-oxo-3-[[(1R)-3-oxocyclopentyl]sulfanyl]-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid	-	Staphylococcus epidermidis
(5S,6S)-6-[(1R)-1-hydroxyethyl]-7-oxo-3-[[(1R)-3-oxocyclopentyl]sulfanyl]-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid	-	Yersinia pestis
(5S,6S)-6-[(1R)-1-hydroxyethyl]-7-oxo-3-[[(3R)-pyrrolidin-3-yl]sulfanyl]-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid	IC50 is 0.00175 mg/l	Escherichia coli
(5S,6S)-6-[(1R)-1-hydroxyethyl]-7-oxo-3-[[(3R)-pyrrolidin-3-yl]sulfanyl]-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid	-	Staphylococcus epidermidis
(5S,6S)-6-[(1R)-1-hydroxyethyl]-7-oxo-3-[[(3R)-pyrrolidin-3-yl]sulfanyl]-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid	-	Yersinia pestis
(5S,6S)-6-[(1R)-1-hydroxyethyl]-7-oxo-3-[[(3S)-pyrrolidin-3-yl]sulfanyl]-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid	IC50 is 0.00080 mg/l	Escherichia coli
(5S,6S)-6-[(1R)-1-hydroxyethyl]-7-oxo-3-[[(3S)-pyrrolidin-3-yl]sulfanyl]-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid	-	Staphylococcus epidermidis
(5S,6S)-6-[(1R)-1-hydroxyethyl]-7-oxo-3-[[(3S)-pyrrolidin-3-yl]sulfanyl]-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid	-	Yersinia pestis
(5S,6S)-6-[(1R)-1-hydroxyethyl]-7-oxo-3-[[2-(pyridin-2-yl)ethyl]sulfanyl]-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid	IC50 is 0.00131 mg/l	Escherichia coli
(5S,6S)-6-[(1R)-1-hydroxyethyl]-7-oxo-3-[[2-(pyridin-2-yl)ethyl]sulfanyl]-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid	-	Staphylococcus epidermidis
(5S,6S)-6-[(1R)-1-hydroxyethyl]-7-oxo-3-[[2-(pyridin-2-yl)ethyl]sulfanyl]-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid	-	Yersinia pestis
(5S,6S)-6-[(2R)-2-hydroxypropyl]-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid	IC50 is 0.00299 mg/l	Escherichia coli
(5S,6S)-6-[(2R)-2-hydroxypropyl]-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid	-	Staphylococcus epidermidis
(5S,6S)-6-[(2R)-2-hydroxypropyl]-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid	-	Yersinia pestis
additional information	beta-lactam antibiotics, one of the most important class of human therapeutics, act via the inhibition of penicillin-binding proteins (PBPs). Bacterial type I signal peptidase is evolutionarily related to the PBPs, but the stereochemistry of its substrates and its catalytic mechanism suggest that beta-lactams with the 5S stereochemistry, as opposed to the 5R stereochemistry of the traditional beta-lactams, are required for inhibition. Synthesis and evaluation of a variety of 5S penem derivatives and identify several with promising activity against both a Gram-positive and a Gram-negative bacterial pathogen, overview. The 5S beta-lactams possess significant antibacterial activity	Escherichia coli
additional information	beta-lactam antibiotics, one of the most important class of human therapeutics, act via the inhibition of penicillin-binding proteins (PBPs). Bacterial type I signal peptidase is evolutionarily related to the PBPs, but the stereochemistry of its substrates and its catalytic mechanism suggest that beta-lactams with the 5S stereochemistry, as opposed to the 5R stereochemistry of the traditional beta-lactams, are required for inhibition. Synthesis and evaluation of a variety of 5S penem derivatives and identify several with promising activity against both a Gram-positive and a Gram-negative bacterial pathogen, overview. The 5S beta-lactams possess significant antibacterial activity, MIC values against Staphylococcus epidermidis, overview	Staphylococcus epidermidis
additional information	beta-lactam antibiotics, one of the most important class of human therapeutics, act via the inhibition of penicillin-binding proteins (PBPs). Bacterial type I signal peptidase is evolutionarily related to the PBPs, but the stereochemistry of its substrates and its catalytic mechanism suggest that beta-lactams with the 5S stereochemistry, as opposed to the 5R stereochemistry of the traditional beta-lactams, are required for inhibition. Synthesis and evaluation of a variety of 5S penem derivatives and identify several with promising activity against both a Gram-positive and a Gram-negative bacterial pathogen, overview. The 5S beta-lactams possess significant antibacterial activity, MIC values against Yersinia pestis, overview	Yersinia pestis
prop-2-en-1-yl (5S,6S)-6-[(2R)-2-hydroxypropyl]-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate	crystal structure of enzyme-bound 1, PDB ID 1B12	Escherichia coli
prop-2-en-1-yl (5S,6S)-6-[(2R)-2-hydroxypropyl]-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate	-	Staphylococcus epidermidis
prop-2-en-1-yl (5S,6S)-6-[(2R)-2-hydroxypropyl]-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate	-	Yersinia pestis

Organism

Organism	UniProt	Comment	Textmining
Escherichia coli	P00803	-	-
Escherichia coli MG1655	P00803	-	-
Staphylococcus epidermidis	-	-	-
Staphylococcus epidermidis RP26A	-	-	-
Yersinia pestis	-	-	-
Yersinia pestis KIM+6	-	-	-

Substrates and Products (Substrate)

Substrates	Comment Substrates	Organism	Products	Comment (Products)	Rev.	Reac.
(4-(4-dimethylaminophenylazo)benzoyl)-AGHDAHASET-(5-((2-aminoethyl)amino)-naphthalene-1-sulfonic acid) + H2O	-	Escherichia coli	(4-(4-dimethylaminophenylazo)benzoyl)-AGHDAHA + SET-(5-((2-aminoethyl)amino)-naphthalene-1-sulfonic acid)	-	?
(4-(4-dimethylaminophenylazo)benzoyl)-AGHDAHASET-(5-((2-aminoethyl)amino)-naphthalene-1-sulfonic acid) + H2O	-	Escherichia coli MG1655	(4-(4-dimethylaminophenylazo)benzoyl)-AGHDAHA + SET-(5-((2-aminoethyl)amino)-naphthalene-1-sulfonic acid)	-	?

Synonyms

Synonyms	Comment	Organism
SPase	-	Staphylococcus epidermidis
SPase	-	Yersinia pestis
SPase	-	Escherichia coli
type I signal peptidase	-	Staphylococcus epidermidis
type I signal peptidase	-	Yersinia pestis
type I signal peptidase	-	Escherichia coli

IC50 Value

IC50 Value	IC50 Value Maximum	Comment	Organism	Inhibitor	Structure
additional information	-	IC50 values of 0.63-3.95 microgram per ml	Escherichia coli	additional information

General Information

General Information	Comment	Organism
evolution	bacterial type I signal peptidase is evolutionarily related to the penicillin-binding proteins (PBPs)	Staphylococcus epidermidis
evolution	bacterial type I signal peptidase is evolutionarily related to the penicillin-binding proteins (PBPs)	Yersinia pestis
evolution	bacterial type I signal peptidase is evolutionarily related to the penicillin-binding proteins (PBPs)	Escherichia coli