Chemistry Commons^™

Cyclobutanone Inhibitors Of Diaminopimelate Desuccinylase (Dape) As Potential New Antibiotics, Thahani Shifna Habeeb Mohammad, Emma H. Kelley, Cory T. Reidl Dr., Katherine Konczak, Megan Beulke, Janielle Javier, Ken W. Olsen, Daniel P. Becker Ph.D.

Chemistry: Faculty Publications and Other Works

Based on our previous success in using cyclobutanone derivatives as enzyme inhibitors, we have designed and prepared a 37-member library of α-aminocyclobutanone amides and sulfonamides, screened for inhibition of the bacterial enzyme diaminopimelate desuccinylase (DapE), which is a promising antibiotic target, and identified several inhibitors with micromolar inhibitory potency. Molecular docking suggests binding of the deprotonated hydrate of the strained cyclobutanone, and thermal shift analysis with the most potent inhibitor (3y, IC50 = 23.1 µM) enabled determination of a Ki value of 10.2 +/− 0.26 µM and observed two separate Tm values for H. influenzae DapE (HiDapE).

Development Of Small Molecule Inhibitors Of Therapeutic Target Enzymes: Paths To Discover Novel Antimicrobials, Thahani Shifna Habeeb Mohammad

Dissertations

The rising antimicrobial resistance to antibiotics is a major global problem, which has been exacerbated by the inappropriate use of antibiotics. The effectiveness of frequently prescribed penicillin derivatives and β-lactamase inhibitors are compromised by the evolution of bacterial β-lactamases and antibiotic-resistant bacteria. Consequently, design and synthesis of small-molecule inhibitors of identified novel antibiotic targets is an urgent unmet medical need. We previously demonstrated that N-functionalized α-aminocyclobutanones can act as peptidomimetic enzyme inhibitors, including inhibition of a key esterase in Francisella Tularensis. The carbonyl of a cyclobutanone is electrophilic due to ring strain, therefore cyclobutanone derivatives can serve as transition state …

Indoline-6-Sulfonamide Inhibitors Of The Bacterial Enzyme Dape, Cory T. Reidl, Tahirah K. Heath, Iman Darwish, Rachel M. Torrez, Maxwell Moore, Elliot Gild, Boguslaw P. Nocek, Anna Starus, Richard C. Holz, Daniel P. Becker Ph.D.

Chemistry: Faculty Publications and Other Works

Inhibitors of the bacterial enzyme dapE-encoded N-succinyl-l,l-diaminopimelic acid desuccinylase (DapE; EC 3.5.1.18) hold promise as antibiotics with a new mechanism of action. Herein we describe the discovery of a new series of indoline sulfonamide DapE inhibitors from a high-throughput screen and the synthesis of a series of analogs. Inhibitory potency was measured by a ninhydrin-based DapE assay recently developed by our group. Molecular docking experiments suggest active site binding with the sulfonamide acting as a zinc-binding group (ZBG).

Indoline‐6‐Sulfonamide Inhibitors Of The Bacterial Enzyme Dape, Cory T. Reidl, Tahirah K. Heath, Iman Darwish, Rachel M. Torrez, Maxwell Moore, Elliot Gild, Boguslaw P. Nocek, Anna Starus, Richard C. Holz, Daniel P. Becker Ph.D.

Chemistry: Faculty Publications and Other Works

Inhibitors of the bacterial enzyme dapE-encoded N-succinyl-l,l-diaminopimelic acid desuccinylase (DapE; EC 3.5.1.18) hold promise as antibiotics with a new mechanism of action. Herein we describe the discovery of a new series of indoline sulfonamide DapE inhibitors from a high-throughput screen and the synthesis of a series of analogs. Inhibitory potency was measured by a ninhydrin-based DapE assay recently developed by our group. Molecular docking experiments suggest active site binding with the sulfonamide acting as a zinc-binding group (ZBG).

Lysine Biosynthesis In Bacteria: A Metallodesuccinylase As A Potential Antimicrobial Target, Danuta M. Gillner, Daniel P. Becker Ph.D., Richard C. Holz

Richard C. Holz

In this review, we summarize the recent literature on dapE-encoded N-succinyl-l,l-diaminopimelic acid desuccinylase (DapE) enzymes, with an emphasis on structure–function studies that provide insight into the catalytic mechanism. Crystallographic data have also provided insight into residues that might be involved in substrate and hence inhibitor recognition and binding. These data have led to the design and synthesis of several new DapE inhibitors, which are described along with what is known about how inhibitors interact with the active site of DapE enzymes, including the efficacy of a moderately strong DapE inhibitor.

The Enzymatic Activity And Inhibition Of Dape Encoded N-Succinyl-L,L-Diaminopimelic Acid Dessucinylase, Tahirah Heath

Dissertations

The bacterial enzyme DapE is a hydrolase in the late stage of the mDAP/lysine biosynthetic pathway that catalyzes the hydrolysis of N-succinyl-L,L-diaminopimelic acid (L,L-SDAP) to succinic acid and L,L-diaminopimelate (DAP). The product DAP is ultimately converted to m-DAP and then to lysine which is used in the construction of proteins, whereas for humans, lysine is an essential amino acid obtained through diet. DapE has been shown to be conserved across many strains of bacteria. The m-DAP produced through the succinylase pathway is used by both gram negative and gram-positive bacteria in the construction of the essential peptidoglycan cell wall. Because …

Application Of Synthetic Organic And Medicinal Chemistry Toward Medical Advances In Cancer, Antibiotics, And Drug Delivery, Marlon Lutz

Dissertations

Cancer and bacterial infections are a great concern in our society and have affected populations worldwide. The objective of this research was to discover new therapies for treating bacterial infections and cancer, and for promoting drug delivery.

DapE is an essential component in succinylase biosynthetic pathway, which is critical to production of lysine and m-DAP which both are essential in protein synthesis and bacterial peptidoglycan cell wall construction. Synthetic approaches were developed to prepare a new substrate for the N-succinyl-L,L-diaminopimelic acid desuccinylase (DapE) enzyme enabling the discovery of new antibiotics that inhibit DapE.

MMPs are over expressed in cancer, in …

Lysine Biosynthesis In Bacteria: A Metallodesuccinylase As A Potential Antimicrobial Target, Danuta Gillner, Daniel P. Becker, Richard C. Holz

Richard C. Holz

In this review, we summarize the recent literature on dapE-encoded N-succinyl-l,l-diaminopimelic acid desuccinylase (DapE) enzymes, with an emphasis on structure–function studies that provide insight into the catalytic mechanism. Crystallographic data have also provided insight into residues that might be involved in substrate and hence inhibitor recognition and binding. These data have led to the design and synthesis of several new DapE inhibitors, which are described along with what is known about how inhibitors interact with the active site of DapE enzymes, including the efficacy of a moderately strong DapE inhibitor.

Lysine Biosynthesis In Bacteria: A Metallodesuccinylase As A Potential Antimicrobial Target, Danuta M. Gillner, Daniel P. Becker Ph.D., Richard C. Holz

Chemistry: Faculty Publications and Other Works

In this review, we summarize the recent literature on dapE-encoded N-succinyl-l,l-diaminopimelic acid desuccinylase (DapE) enzymes, with an emphasis on structure–function studies that provide insight into the catalytic mechanism. Crystallographic data have also provided insight into residues that might be involved in substrate and hence inhibitor recognition and binding. These data have led to the design and synthesis of several new DapE inhibitors, which are described along with what is known about how inhibitors interact with the active site of DapE enzymes, including the efficacy of a moderately strong DapE inhibitor.

Lysine Biosynthesis In Bacteria: A Metallodesuccinylase As A Potential Antimicrobial Target, Danuta Gillner, Daniel P. Becker, Richard C. Holz

Chemistry Faculty Research and Publications

In this review, we summarize the recent literature on dapE-encoded N-succinyl-l,l-diaminopimelic acid desuccinylase (DapE) enzymes, with an emphasis on structure–function studies that provide insight into the catalytic mechanism. Crystallographic data have also provided insight into residues that might be involved in substrate and hence inhibitor recognition and binding. These data have led to the design and synthesis of several new DapE inhibitors, which are described along with what is known about how inhibitors interact with the active site of DapE enzymes, including the efficacy of a moderately strong DapE inhibitor.

Inhibitors Of Bacterial N-Succinyl-L,L-Diaminopimelic Acid Desuccinylase (Dape) And Demonstration Of In Vitro Antimicrobial Activity, Danuta Gillner, Nicola Armoush, Richard C. Holz, Daniel P. Becker

Chemistry Faculty Research and Publications

The dapE-encoded N-succinyl-L,L-diaminopimelic acid desuccinylase (DapE) is a critical bacterial enzyme for the construction of the bacterial cell wall. A screen biased toward compounds containing zinc-binding groups (ZBG’s) including thiols, carboxylic acids, boronic acids, phosphonates and hydroxamates has delivered a number of micromolar inhibitors of DapE from Haemophilus influenzae, including the low micromolar inhibitor L-captopril (IC₅₀ = 3.3 μM, K_i = 1.8 μM). In vitro antimicrobial activity was demonstrated for l-captopril against Escherichia coli.