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Article ; Online: Formulation studies of InhA inhibitors and combination therapy to improve efficacy against Mycobacterium tuberculosis.

Knudson, Susan E / Cummings, Jason E / Bommineni, Gopal R / Pan, Pan / Tonge, Peter J / Slayden, Richard A

2016 Volume 101, Page(s) 8–14

Abstract: Previously, structure-based drug design was used to develop substituted diphenyl ethers with potency against the Mycobacterium tuberculosis (Mtb) enoyl-ACP reductase (InhA), however, the highly lipophilic centroid compound, SB-PT004, lacked sufficient ... ...

Abstract	Previously, structure-based drug design was used to develop substituted diphenyl ethers with potency against the Mycobacterium tuberculosis (Mtb) enoyl-ACP reductase (InhA), however, the highly lipophilic centroid compound, SB-PT004, lacked sufficient efficacy in the acute murine Mtb infection model. A next generation series of compounds were designed with improved specificity, potency against InhA, and reduced cytotoxicity in vitro, but these compounds also had limited solubility. Accordingly, solubility and pharmacokinetics studies were performed to develop formulations for this class and other experimental drug candidates with high logP values often encountered in drug discovery. Lead diphenyl ethers were formulated in co-solvent and Self-Dispersing Lipid Formulations (SDLFs) and evaluated in a rapid murine Mtb infection model that assesses dissemination to and bacterial burden in the spleen. In vitro synergy studies were performed with the lead diphenyl ether compounds, SB-PT070 and SB-PT091, and rifampin (RIF), which demonstrated an additive effect, and that guided the in vivo studies. Combinatorial therapy in vivo studies with these compounds delivered in our Self-Micro Emulsifying Drug Delivery System (SMEDDS) resulted in an additional 1.4 log
MeSH term(s)	Animals ; Antitubercular Agents/blood ; Antitubercular Agents/pharmacology ; Bacterial Proteins/antagonists & inhibitors ; Disease Models, Animal ; Drug Compounding ; Drug Delivery Systems ; Drug Discovery/methods ; Drug Synergism ; Drug Therapy, Combination ; Emulsifying Agents ; Mice, Inbred C57BL ; Microbial Sensitivity Tests/methods ; Mycobacterium tuberculosis/drug effects ; Oxidoreductases/antagonists & inhibitors ; Phenyl Ethers/blood ; Phenyl Ethers/pharmacology ; Solubility ; Spleen/microbiology ; Tuberculosis/blood ; Tuberculosis/drug therapy ; Tuberculosis/microbiology
Chemical Substances	Antitubercular Agents ; Bacterial Proteins ; Emulsifying Agents ; Phenyl Ethers ; Oxidoreductases (EC 1.-) ; InhA protein, Mycobacterium (EC 1.3.1.9)
Language	English
Publishing date	2016-12
Publishing country	Scotland
Document type	Journal Article
ZDB-ID	2046804-0
ISSN	1873-281X ; 1472-9792
ISSN (online)	1873-281X
ISSN	1472-9792
DOI	10.1016/j.tube.2016.07.016
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Article ; Online: Structural basis for the synergy of 4'- and 2'-modifications on siRNA nuclease resistance, thermal stability and RNAi activity.

Harp, Joel M / Guenther, Dale C / Bisbe, Anna / Perkins, Lydia / Matsuda, Shigeo / Bommineni, Gopal R / Zlatev, Ivan / Foster, Donald J / Taneja, Nate / Charisse, Klaus / Maier, Martin A / Rajeev, Kallanthottathil G / Manoharan, Muthiah / Egli, Martin

Nucleic acids research

2018 Volume 46, Issue 16, Page(s) 8090–8104

Abstract: Chemical modification is a prerequisite of oligonucleotide therapeutics for improved metabolic stability, uptake and activity, irrespective of their mode of action, i.e. antisense, RNAi or aptamer. Phosphate moiety and ribose C2'/O2' atoms are the most ... ...

Abstract	Chemical modification is a prerequisite of oligonucleotide therapeutics for improved metabolic stability, uptake and activity, irrespective of their mode of action, i.e. antisense, RNAi or aptamer. Phosphate moiety and ribose C2'/O2' atoms are the most common sites for modification. Compared to 2'-O-substituents, ribose 4'-C-substituents lie in proximity of both the 3'- and 5'-adjacent phosphates. To investigate potentially beneficial effects on nuclease resistance we combined 2'-F and 2'-OMe with 4'-Cα- and 4'-Cβ-OMe, and 2'-F with 4'-Cα-methyl modification. The α- and β-epimers of 4'-C-OMe-uridine and the α-epimer of 4'-C-Me-uridine monomers were synthesized and incorporated into siRNAs. The 4'α-epimers affect thermal stability only minimally and show increased nuclease stability irrespective of the 2'-substituent (H, F, OMe). The 4'β-epimers are strongly destabilizing, but afford complete resistance against an exonuclease with the phosphate or phosphorothioate backbones. Crystal structures of RNA octamers containing 2'-F,4'-Cα-OMe-U, 2'-F,4'-Cβ-OMe-U, 2'-OMe,4'-Cα-OMe-U, 2'-OMe,4'-Cβ-OMe-U or 2'-F,4'-Cα-Me-U help rationalize these observations and point to steric and electrostatic origins of the unprecedented nuclease resistance seen with the chain-inverted 4'β-U epimer. We used structural models of human Argonaute 2 in complex with guide siRNA featuring 2'-F,4'-Cα-OMe-U or 2'-F,4'-Cβ-OMe-U at various sites in the seed region to interpret in vitro activities of siRNAs with the corresponding 2'-/4'-C-modifications.
MeSH term(s)	Humans ; Models, Molecular ; Nucleic Acid Conformation ; Oligonucleotides/chemistry ; Oligonucleotides/genetics ; Phosphates/chemistry ; RNA Interference ; RNA Stability/genetics ; RNA, Small Interfering/chemistry ; Ribonucleases/chemistry ; Ribose/chemistry ; Thermodynamics ; Uridine/chemistry ; Uridine/genetics
Chemical Substances	Oligonucleotides ; Phosphates ; RNA, Small Interfering ; Ribose (681HV46001) ; Ribonucleases (EC 3.1.-) ; Uridine (WHI7HQ7H85)
Language	English
Publishing date	2018-08-11
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	186809-3
ISSN	1362-4962 ; 1362-4954 ; 0301-5610 ; 0305-1048
ISSN (online)	1362-4962 ; 1362-4954
ISSN	0301-5610 ; 0305-1048
DOI	10.1093/nar/gky703
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Article: The Francisella tularensis FabI Enoyl-Acyl Carrier Protein Reductase Gene Is Essential to Bacterial Viability and Is Expressed during Infection

Kingry, Luke C / Cummings, Jason E / Brookman, Kerry W / Bommineni, Gopal R / Tonge, Peter J / Slayden, Richard A

Journal of bacteriology. 2013 Jan. 15, v. 195, no. 2

2013

Abstract: Francisella tularensis is classified as a category A priority pathogen and causes fatal disseminated disease in humans upon inhalation of less than 50 bacteria. Although drugs are available for treatment, they are not ideal because of toxicity and route ... ...

Abstract	Francisella tularensis is classified as a category A priority pathogen and causes fatal disseminated disease in humans upon inhalation of less than 50 bacteria. Although drugs are available for treatment, they are not ideal because of toxicity and route of delivery, and in some cases patients relapse upon withdrawal. We have an ongoing program to develop novel FAS-II FabI enoyl-ACP reductase enzyme inhibitors for Francisella and other select agents. To establish F. tularensis FabI (FtFabI) as a clinically relevant drug target, we demonstrated that fatty acid biosynthesis and FabI activity are essential for growth even in the presence of exogenous long-chain lipids and that FtfabI is not transcriptionally altered in the presence of exogenous long-chain lipids. Inhibition of FtFabI or fatty acid synthesis results in loss of viability that is not rescued by exogenous long-chain lipid supplementation. Importantly, whole-genome transcriptional profiling of F. tularensis with DNA microarrays from infected tissues revealed that FtfabI and de novo fatty acid biosynthetic genes are transcriptionally active during infection. This is the first demonstration that the FabI enoyl-ACP-reductase enzyme encoded by F. tularensis is essential and not bypassed by exogenous fatty acids and that de novo fatty acid biosynthetic components encoded in F. tularensis are transcriptionally active during infection in the mouse model of tularemia.
Keywords	DNA microarrays ; Francisella tularensis ; animal models ; bacteria ; bacteriology ; biosynthesis ; breathing ; drugs ; enzyme inhibitors ; fatty acids ; genes ; humans ; pathogens ; patients ; relapse ; toxicity ; transcription (genetics) ; tularemia ; viability
Language	English
Dates of publication	2013-0115
Size	p. 351-358.
Publishing place	American Society for Microbiology
Document type	Article
ZDB-ID	2968-3
ISSN	1098-5530 ; 0021-9193
ISSN (online)	1098-5530
ISSN	0021-9193
DOI	10.1128/JB.01957-12
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Article: Rational Modulation of the Induced-Fit Conformational Change for Slow-Onset Inhibition in Mycobacterium tuberculosis InhA

Lai, Cheng-Tsung / Li Huei-Jiun / Yu Weixuan / Shah Sonam / Bommineni Gopal R / Perrone Victoria / Garcia-Diaz Miguel / Tonge Peter J / Simmerling Carlos

Biochemistry. 2015 Aug. 04, v. 54, no. 30

2015

Abstract: Slow-onset enzyme inhibitors are the subject of considerable interest as an approach to increasing the potency of pharmaceutical compounds by extending the residence time of the inhibitor on the target (the lifetime of the drugâreceptor complex). ... ...

Abstract	Slow-onset enzyme inhibitors are the subject of considerable interest as an approach to increasing the potency of pharmaceutical compounds by extending the residence time of the inhibitor on the target (the lifetime of the drugâreceptor complex). However, rational modulation of residence time presents significant challenges because it requires additional mechanistic insight, such as the nature of the transition state for postbinding isomerization. Our previous work, based on X-ray crystallography, enzyme kinetics, and molecular dynamics simulation, suggested that the slow step in inhibition of the Mycobacterium tuberculosis enoyl-ACP reductase InhA involves a change in the conformation of the substrate binding loop from an open state in the initial enzymeâinhibitor complex to a closed state in the final enzymeâinhibitor complex. Here, we use multidimensional free energy landscapes for loop isomerization to obtain a computational model for the transition state. The results suggest that slow-onset inhibitors crowd key side chains on helices that slide past each other during isomerization, resulting in a steric clash. The landscapes become significantly flatter when residues involved in the steric clash are replaced with alanine. Importantly, this lower barrier can be increased by rational inhibitor redesign to restore the steric clash. Crystallographic studies and enzyme kinetics confirm the predicted effects on loop structure and flexibility, as well as inhibitor residence time. These loss and regain of function studies validate our mechanistic hypothesis for interactions controlling substrate binding loop isomerization, providing a platform for the future design of inhibitors with longer residence times and better in vivo potency. Similar opportunities for slow-onset inhibition via the same mechanism are identified in other pathogens.
Keywords	Mycobacterium tuberculosis ; X-ray diffraction ; alanine ; drugs ; enoyl-(acyl-carrier-protein) reductase (NADH) ; enzyme inhibitors ; enzyme kinetics ; isomerization ; models ; molecular dynamics ; pathogens
Language	English
Dates of publication	2015-0804
Size	p. 4683-4691.
Publishing place	American Chemical Society
Document type	Article
ZDB-ID	1108-3
ISSN	1520-4995 ; 0006-2960
ISSN (online)	1520-4995
ISSN	0006-2960
DOI	10.1021%2Facs.biochem.5b00284
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Article ; Online: Rationalizing the Binding Kinetics for the Inhibition of the Burkholderia pseudomallei FabI1 Enoyl-ACP Reductase.

Neckles, Carla / Eltschkner, Sandra / Cummings, Jason E / Hirschbeck, Maria / Daryaee, Fereidoon / Bommineni, Gopal R / Zhang, Zhuo / Spagnuolo, Lauren / Yu, Weixuan / Davoodi, Shabnam / Slayden, Richard A / Kisker, Caroline / Tonge, Peter J

Biochemistry

2017 Volume 56, Issue 13, Page(s) 1865–1878

Abstract: There is growing awareness of the link between drug-target residence time and in vivo drug activity, and there are increasing efforts to determine the molecular factors that control the lifetime of a drug-target complex. Rational alterations in the drug- ... ...

Abstract	There is growing awareness of the link between drug-target residence time and in vivo drug activity, and there are increasing efforts to determine the molecular factors that control the lifetime of a drug-target complex. Rational alterations in the drug-target residence time require knowledge of both the ground and transition states on the inhibition reaction coordinate, and we have determined the structure-kinetic relationship for 22 ethyl- or hexyl-substituted diphenyl ethers that are slow-binding inhibitors of bpFabI1, the enoyl-ACP reductase FabI1 from Burkholderia pseudomallei. Analysis of enzyme inhibition using a two-dimensional kinetic map demonstrates that the ethyl and hexyl diphenyl ethers fall into two distinct clusters. Modifications to the ethyl diphenyl ether B ring result in changes to both on and off rates, where residence times of up to ∼700 min (∼11 h) are achieved by either ground state stabilization (PT444) or transition state destabilization (slower on rate) (PT404). By contrast, modifications to the hexyl diphenyl ether B ring result in residence times of 300 min (∼5 h) through changes in only ground state stabilization (PT119). Structural analysis of nine enzyme:inhibitor complexes reveals that the variation in structure-kinetic relationships can be rationalized by structural rearrangements of bpFabI1 and subtle changes to the orientation of the inhibitor in the binding pocket. Finally, we demonstrate that three compounds with residence times on bpFabI1 from 118 min (∼2 h) to 670 min (∼11 h) have in vivo efficacy in an acute B. pseudomallei murine infection model using the virulent B. pseudomallei strain Bp400.
MeSH term(s)	Animals ; Anti-Bacterial Agents/chemistry ; Anti-Bacterial Agents/pharmacology ; Bacterial Proteins/antagonists & inhibitors ; Bacterial Proteins/genetics ; Bacterial Proteins/metabolism ; Binding Sites ; Burkholderia pseudomallei/drug effects ; Burkholderia pseudomallei/enzymology ; Burkholderia pseudomallei/genetics ; Burkholderia pseudomallei/growth & development ; Colony Count, Microbial ; Crystallography, X-Ray ; Enoyl-(Acyl-Carrier-Protein) Reductase (NADH)/antagonists & inhibitors ; Enoyl-(Acyl-Carrier-Protein) Reductase (NADH)/genetics ; Enoyl-(Acyl-Carrier-Protein) Reductase (NADH)/metabolism ; Enzyme Inhibitors/chemistry ; Enzyme Inhibitors/pharmacology ; Female ; Gene Expression ; Kinetics ; Lung/drug effects ; Lung/microbiology ; Melioidosis/diet therapy ; Melioidosis/drug therapy ; Melioidosis/microbiology ; Mice ; Mice, Inbred BALB C ; Microbial Sensitivity Tests ; Molecular Dynamics Simulation ; Phenyl Ethers/chemistry ; Phenyl Ethers/pharmacology ; Protein Binding ; Protein Structure, Secondary ; Spleen/drug effects ; Spleen/microbiology ; Structure-Activity Relationship
Chemical Substances	Anti-Bacterial Agents ; Bacterial Proteins ; Enzyme Inhibitors ; Phenyl Ethers ; Enoyl-(Acyl-Carrier-Protein) Reductase (NADH) (EC 1.3.1.9)
Language	English
Publishing date	2017-03-21
Publishing country	United States
Document type	Journal Article ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1108-3
ISSN	1520-4995 ; 0006-2960
ISSN (online)	1520-4995
ISSN	0006-2960
DOI	10.1021/acs.biochem.6b01048
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Article: Rationalizing the Binding Kinetics for the Inhibition of the Burkholderia pseudomallei FabI1 Enoyl-ACP Reductase

Neckles, Carla / Bommineni Gopal R / Cummings Jason E / Daryaee Fereidoon / Davoodi Shabnam / Eltschkner Sandra / Hirschbeck Maria / Kisker Caroline / Slayden Richard A / Spagnuolo Lauren / Tonge Peter J / Yu Weixuan / Zhang Zhuo

Biochemistry. 2017 Apr. 04, v. 56, no. 13

2017

Abstract: There is growing awareness of the link between drugâtarget residence time and in vivo drug activity, and there are increasing efforts to determine the molecular factors that control the lifetime of a drugâtarget complex. Rational alterations in the ... ...

Abstract	There is growing awareness of the link between drugâtarget residence time and in vivo drug activity, and there are increasing efforts to determine the molecular factors that control the lifetime of a drugâtarget complex. Rational alterations in the drugâtarget residence time require knowledge of both the ground and transition states on the inhibition reaction coordinate, and we have determined the structureâkinetic relationship for 22 ethyl- or hexyl-substituted diphenyl ethers that are slow-binding inhibitors of bpFabI1, the enoyl-ACP reductase FabI1 from Burkholderia pseudomallei. Analysis of enzyme inhibition using a two-dimensional kinetic map demonstrates that the ethyl and hexyl diphenyl ethers fall into two distinct clusters. Modifications to the ethyl diphenyl ether B ring result in changes to both on and off rates, where residence times of up to â¼700 min (â¼11 h) are achieved by either ground state stabilization (PT444) or transition state destabilization (slower on rate) (PT404). By contrast, modifications to the hexyl diphenyl ether B ring result in residence times of 300 min (â¼5 h) through changes in only ground state stabilization (PT119). Structural analysis of nine enzyme:inhibitor complexes reveals that the variation in structureâkinetic relationships can be rationalized by structural rearrangements of bpFabI1 and subtle changes to the orientation of the inhibitor in the binding pocket. Finally, we demonstrate that three compounds with residence times on bpFabI1 from 118 min (â¼2 h) to 670 min (â¼11 h) have in vivo efficacy in an acute B. pseudomallei murine infection model using the virulent B. pseudomallei strain Bp400.
Keywords	Burkholderia pseudomallei ; diphenyl ethers ; drugs ; enoyl-(acyl-carrier-protein) reductase (NADH) ; enzyme inhibition ; mice ; models ; virulence
Language	English
Dates of publication	2017-0404
Size	p. 1865-1878.
Publishing place	American Chemical Society
Document type	Article
ZDB-ID	1108-3
ISSN	1520-4995 ; 0006-2960
ISSN (online)	1520-4995
ISSN	0006-2960
DOI	10.1021%2Facs.biochem.6b01048
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Article ; Online: Thiolactomycin-based β-ketoacyl-AcpM synthase A (KasA) inhibitors: fragment-based inhibitor discovery using transient one-dimensional nuclear overhauser effect NMR spectroscopy.

Kapilashrami, Kanishk / Bommineni, Gopal R / Machutta, Carl A / Kim, Pilho / Lai, Cheng-Tsung / Simmerling, Carlos / Picart, Francis / Tonge, Peter J

The Journal of biological chemistry

2013 Volume 288, Issue 9, Page(s) 6045–6052

Abstract: Thiolactomycin (TLM) is a natural product inhibitor of KasA, the β-ketoacyl synthase A from Mycobacterium tuberculosis. To improve the affinity of TLM for KasA, a series of TLM analogs have been synthesized based on interligand NOEs between TLM and a ... ...

Abstract	Thiolactomycin (TLM) is a natural product inhibitor of KasA, the β-ketoacyl synthase A from Mycobacterium tuberculosis. To improve the affinity of TLM for KasA, a series of TLM analogs have been synthesized based on interligand NOEs between TLM and a pantetheine analog when both are bound simultaneously to the enzyme. Kinetic binding data reveal that position 3 of the thiolactone ring is a suitable position for elaboration of the TLM scaffold, and the structure-activity relationship studies provide information on the molecular features that govern time-dependent inhibition in this enzyme system. These experiments also exemplify the utility of transient one-dimensional NOE spectroscopy for obtaining interligand NOEs compared with traditional steady state two-dimensional NOESY spectroscopy.
MeSH term(s)	3-Oxoacyl-(Acyl-Carrier-Protein) Synthase/antagonists & inhibitors ; 3-Oxoacyl-(Acyl-Carrier-Protein) Synthase/genetics ; 3-Oxoacyl-(Acyl-Carrier-Protein) Synthase/metabolism ; Bacterial Proteins/antagonists & inhibitors ; Bacterial Proteins/genetics ; Bacterial Proteins/metabolism ; Enzyme Inhibitors/chemical synthesis ; Enzyme Inhibitors/chemistry ; Mycobacterium smegmatis/enzymology ; Mycobacterium smegmatis/genetics ; Mycobacterium tuberculosis/enzymology ; Mycobacterium tuberculosis/genetics ; Protein Binding ; Structure-Activity Relationship ; Thiophenes/chemical synthesis ; Thiophenes/chemistry
Chemical Substances	Bacterial Proteins ; Enzyme Inhibitors ; Thiophenes ; thiolactomycin (82079-32-1) ; 3-Oxoacyl-(Acyl-Carrier-Protein) Synthase (EC 2.3.1.41)
Language	English
Publishing date	2013-01-10
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1074/jbc.M112.414516
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Article ; Online: Structural basis for the recognition of mycolic acid precursors by KasA, a condensing enzyme and drug target from Mycobacterium tuberculosis.

Schiebel, Johannes / Kapilashrami, Kanishk / Fekete, Agnes / Bommineni, Gopal R / Schaefer, Christin M / Mueller, Martin J / Tonge, Peter J / Kisker, Caroline

The Journal of biological chemistry

2013 Volume 288, Issue 47, Page(s) 34190–34204

Abstract: The survival of Mycobacterium tuberculosis depends on mycolic acids, very long α-alkyl-β-hydroxy fatty acids comprising 60-90 carbon atoms. However, despite considerable efforts, little is known about how enzymes involved in mycolic acid biosynthesis ... ...

Abstract	The survival of Mycobacterium tuberculosis depends on mycolic acids, very long α-alkyl-β-hydroxy fatty acids comprising 60-90 carbon atoms. However, despite considerable efforts, little is known about how enzymes involved in mycolic acid biosynthesis recognize and bind their hydrophobic fatty acyl substrates. The condensing enzyme KasA is pivotal for the synthesis of very long (C38-42) fatty acids, the precursors of mycolic acids. To probe the mechanism of substrate and inhibitor recognition by KasA, we determined the structure of this protein in complex with a mycobacterial phospholipid and with several thiolactomycin derivatives that were designed as substrate analogs. Our structures provide consecutive snapshots along the reaction coordinate for the enzyme-catalyzed reaction and support an induced fit mechanism in which a wide cavity is established through the concerted opening of three gatekeeping residues and several α-helices. The stepwise characterization of the binding process provides mechanistic insights into the induced fit recognition in this system and serves as an excellent foundation for the development of high affinity KasA inhibitors.
MeSH term(s)	Antitubercular Agents/chemistry ; Antitubercular Agents/therapeutic use ; Drug Delivery Systems ; Enzyme Inhibitors/chemistry ; Enzyme Inhibitors/therapeutic use ; Fatty Acid Synthases/antagonists & inhibitors ; Fatty Acid Synthases/chemistry ; Fatty Acid Synthases/metabolism ; Mycobacterium tuberculosis/enzymology ; Mycolic Acids/chemistry ; Mycolic Acids/metabolism ; Protein Structure, Secondary ; Protein Structure, Tertiary ; Tuberculosis/drug therapy ; Tuberculosis/enzymology
Chemical Substances	Antitubercular Agents ; Enzyme Inhibitors ; Mycolic Acids ; Fatty Acid Synthases (EC 2.3.1.85)
Language	English
Publishing date	2013-10-09
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1074/jbc.M113.511436
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Article ; Online: Thiolactomycin-Based Inhibitors of Bacterial β-Ketoacyl-ACP Synthases with in Vivo Activity.

Bommineni, Gopal R / Kapilashrami, Kanishk / Cummings, Jason E / Lu, Yang / Knudson, Susan E / Gu, Chendi / Walker, Stephen G / Slayden, Richard A / Tonge, Peter J

Journal of medicinal chemistry

2016 Volume 59, Issue 11, Page(s) 5377–5390

Abstract: β-Ketoacyl-ACP synthases (KAS) are key enzymes involved in the type II bacterial fatty acid biosynthesis (FASII) pathway and are putative targets for antibacterial discovery. Several natural product KAS inhibitors have previously been reported, including ...

Abstract	β-Ketoacyl-ACP synthases (KAS) are key enzymes involved in the type II bacterial fatty acid biosynthesis (FASII) pathway and are putative targets for antibacterial discovery. Several natural product KAS inhibitors have previously been reported, including thiolactomycin (TLM), which is produced by Nocardia spp. Here we describe the synthesis and characterization of optically pure 5R-thiolactomycin (TLM) analogues that show improved whole cell activity against bacterial strains including methicillin-resistant Staphylococcus aureus (MRSA) and priority pathogens such as Francisella tularensis and Burkholderia pseudomallei. In addition, we identify TLM analogues with in vivo efficacy against MRSA and Klebsiella pneumoniae in animal models of infection.
MeSH term(s)	3-Oxoacyl-(Acyl-Carrier-Protein) Synthase/antagonists & inhibitors ; 3-Oxoacyl-(Acyl-Carrier-Protein) Synthase/metabolism ; Animals ; Anti-Bacterial Agents/chemical synthesis ; Anti-Bacterial Agents/chemistry ; Anti-Bacterial Agents/pharmacology ; Burkholderia pseudomallei/drug effects ; Burkholderia pseudomallei/enzymology ; Cell Line ; Disease Models, Animal ; Dose-Response Relationship, Drug ; Enzyme Inhibitors/chemical synthesis ; Enzyme Inhibitors/chemistry ; Enzyme Inhibitors/pharmacology ; Francisella tularensis/drug effects ; Francisella tularensis/enzymology ; Humans ; Klebsiella Infections/drug therapy ; Klebsiella pneumoniae/drug effects ; Klebsiella pneumoniae/enzymology ; Male ; Methicillin-Resistant Staphylococcus aureus/drug effects ; Methicillin-Resistant Staphylococcus aureus/enzymology ; Mice ; Microbial Sensitivity Tests ; Molecular Conformation ; Staphylococcal Infections/drug therapy ; Staphylococcus aureus/drug effects ; Staphylococcus aureus/enzymology ; Structure-Activity Relationship ; Thiophenes/chemical synthesis ; Thiophenes/chemistry ; Thiophenes/pharmacology ; Yersinia pestis/drug effects ; Yersinia pestis/enzymology
Chemical Substances	Anti-Bacterial Agents ; Enzyme Inhibitors ; Thiophenes ; thiolactomycin (82079-32-1) ; 3-Oxoacyl-(Acyl-Carrier-Protein) Synthase (EC 2.3.1.41)
Language	English
Publishing date	2016-06-09
Publishing country	United States
Document type	Journal Article
ZDB-ID	218133-2
ISSN	1520-4804 ; 0022-2623
ISSN (online)	1520-4804
ISSN	0022-2623
DOI	10.1021/acs.jmedchem.6b00236
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Article: Selectivity of Pyridone- and Diphenyl Ether-Based Inhibitors for the Yersinia pestis FabV Enoyl-ACP Reductase

Neckles, Carla / Pschibul Annica / Lai Cheng-Tsung / Hirschbeck Maria / Kuper Jochen / Davoodi Shabnam / Zou Junjie / Liu Nina / Pan Pan / Shah Sonam / Daryaee Fereidoon / Bommineni Gopal R / Lai Cristina / Simmerling Carlos / Kisker Caroline / Tonge Peter J

Biochemistry. 2016 May 31, v. 55, no. 21

2016

Abstract: The enoyl-ACP reductase (ENR) catalyzes the last reaction in the elongation cycle of the bacterial type II fatty acid biosynthesis (FAS-II) pathway. While the FabI ENR is a well-validated drug target in organisms such as Mycobacterium tuberculosis and ... ...

Abstract	The enoyl-ACP reductase (ENR) catalyzes the last reaction in the elongation cycle of the bacterial type II fatty acid biosynthesis (FAS-II) pathway. While the FabI ENR is a well-validated drug target in organisms such as Mycobacterium tuberculosis and Staphylococcus aureus, alternate ENR isoforms have been discovered in other pathogens, including the FabV enzyme that is the sole ENR in Yersinia pestis (ypFabV). Previously, we showed that the prototypical ENR inhibitor triclosan was a poor inhibitor of ypFabV and that inhibitors based on the 2-pyridone scaffold were more potent [Hirschbeck, M. (2012) Structure 20 (1), 89â100]. These studies were performed with the T276S FabV variant. In the work presented here, we describe a detailed examination of the mechanism and inhibition of wild-type ypFabV and the T276S variant. The T276S mutation significantly reduces the affinity of diphenyl ether inhibitors for ypFabV (20-fold â 100-fold). In addition, while T276S ypFabV generally displays an affinity for 2-pyridone inhibitors higher than that of the wild-type enzyme, the 4-pyridone scaffold yields compounds with similar affinity for both wild-type and T276S ypFabV. T276 is located at the N-terminus of the helical substrate-binding loop, and structural studies coupled with site-directed mutagenesis reveal that alterations in this residue modulate the size of the active site portal. Subsequently, we were able to probe the mechanism of time-dependent inhibition in this enzyme family by extending the inhibition studies to include P142W ypFabV, a mutation that results in a gain of slow-onset inhibition for the 4-pyridone PT156.
Keywords	Mycobacterium tuberculosis ; Staphylococcus aureus ; Yersinia pestis ; active sites ; biosynthesis ; biphenyl ; diphenyl ethers ; drugs ; enoyl-(acyl-carrier-protein) reductase (NADH) ; enzyme inhibition ; fatty acids ; pathogens ; site-directed mutagenesis
Language	English
Dates of publication	2016-0531
Size	p. 2992-3006.
Publishing place	American Chemical Society
Document type	Article
ZDB-ID	1108-3
ISSN	1520-4995 ; 0006-2960
ISSN (online)	1520-4995
ISSN	0006-2960
DOI	10.1021%2Facs.biochem.5b01301
Database	NAL-Catalogue (AGRICOLA)

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