Design, Synthesis, and Antibacterial Properties of Dual-Ligand Inhibitors of Acetyl-CoA Carboxylase

Silvers, Molly A.; Robertson, Gregory T.; Taylor, Carol M.; Waldrop, Grover L.

doi:10.1021/jm501082n

Cited by 28 publications

(29 citation statements)

References 43 publications

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“…Succinimide ( 3 ) is commercially available, and (3 S )-methyl succinimide ( 4 ) was synthesized from an intermediate precursor during the synthesis of moiramide B (compound 1 ). 16 Compounds 5 and 6 were also intermediates generated during the synthesis of moiramide B (compound 1 ). 16 Compound 7 , a stand-alone version of the “tail” fragment, was synthesized for this analysis.…”

Section: Resultsmentioning

confidence: 99%

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Crystal Structure of Carboxyltransferase from Staphylococcus aureus Bound to the Antibacterial Agent Moiramide B

Silvers¹,

Pakhomova²,

Neau

et al. 2016

Biochemistry

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The dramatic increase in the prevalence of antibiotic-resistant bacteria has necessitated a search for new antibacterial agents against novel targets. Moiramide B is a natural product, broad-spectrum antibiotic that inhibits the carboxyltransferase component of acetyl-CoA carboxylase, which catalyzes the first committed step in fatty acid synthesis. Herein, we report the 2.6 Å resolution crystal structure of moiramide B bound to carboxyltransferase. An unanticipated but significant finding was that moiramide B bound as the enol/enolate. Crystallographic studies demonstrate that the (4S)-methyl succinimide moiety interacts with the oxyanion holes of the enzyme, supporting the notion that an anionic enolate is the active form of the antibacterial agent. Structure–activity studies demonstrate that the unsaturated fatty acid tail of moiramide B is needed only for entry into the bacterial cell. These results will allow the design of new antibacterial agents against the bacterial form of carboxyltransferase.

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Section: Resultsmentioning

confidence: 99%

“…16 Compounds 5 and 6 were also intermediates generated during the synthesis of moiramide B (compound 1 ). 16 Compound 7 , a stand-alone version of the “tail” fragment, was synthesized for this analysis.…”

Section: Resultsmentioning

confidence: 99%

Crystal Structure of Carboxyltransferase from Staphylococcus aureus Bound to the Antibacterial Agent Moiramide B

Silvers¹,

Pakhomova²,

Neau

et al. 2016

Biochemistry

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“…Tn-seq fitness data presented in this work might aid in this work by identifying potential antibody targets whose inactivation by binding would impair essential pathways. Similarly, small molecule inhibitors of bacterial intracellular signaling and/or metabolic pathways have been proposed as novel antibiotics or adjuvants [ 42 – 44 ]. The search for novel drug targets may benefit from access to fitness data such as ours.…”

Section: Discussionmentioning

confidence: 99%

The essential genome of Streptococcus agalactiae

et al. 2016

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BackgroundNext-generation sequencing of transposon-genome junctions from a saturated bacterial mutant library (Tn-seq) is a powerful tool that permits genome-wide determination of the contribution of genes to fitness of the organism under a wide range of experimental conditions. We report development, testing, and results from a Tn-seq system for use in Streptococcus agalactiae (group B Streptococcus; GBS), an important cause of neonatal sepsis.MethodsOur method uses a Himar1 mini-transposon that inserts at genomic TA dinucleotide sites, delivered to GBS on a temperature-sensitive plasmid that is subsequently cured from the bacterial population. In order to establish the GBS essential genome, we performed Tn-seq on DNA collected from three independent mutant libraries—with at least 135,000 mutants per library—at serial 24 h time points after outgrowth in rich media.ResultsAfter statistical analysis of transposon insertion density and distribution, we identified 13.5 % of genes as essential and 1.2 % as critical, with high levels of reproducibility. Essential and critical genes are enriched for fundamental cellular housekeeping functions, such as acyl-tRNA biosynthesis, nucleotide metabolism, and glycolysis. We further validated our system by comparing fitness assignments of homologous genes in GBS and a close bacterial relative, Streptococcus pyogenes, which demonstrated 93 % concordance. Finally, we used our fitness assignments to identify signal transduction pathway components predicted to be essential or critical in GBS.ConclusionsWe believe that our baseline fitness assignments will be a valuable tool for GBS researchers and that our system has the potential to reveal key pathogenesis gene networks and potential therapeutic/preventative targets.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-016-2741-z) contains supplementary material, which is available to authorized users.

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“…(reviewed by (166)). Acetyl-CoA carboxylase is comprised of two enzymes, biotin carboxylase and carboxyltransferase, and catalyzes the first committed step in fatty acid synthesis (167). Acetyl-CoA carboxylase is an antimicrobial target in M. tuberculosis (168), E. coli (169,170), other bacteria and most living organisms (reviewed by (171)).…”

Section: Discussionmentioning

confidence: 99%

In silicoidentification of metabolic enzyme drug targets inBurkholderia pseudomallei

Challacombe

2015

Preprint

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Design, Synthesis, and Antibacterial Properties of Dual-Ligand Inhibitors of Acetyl-CoA Carboxylase

Cited by 28 publications

References 43 publications

Crystal Structure of Carboxyltransferase from Staphylococcus aureus Bound to the Antibacterial Agent Moiramide B

Crystal Structure of Carboxyltransferase from Staphylococcus aureus Bound to the Antibacterial Agent Moiramide B

The essential genome of Streptococcus agalactiae

In silicoidentification of metabolic enzyme drug targets inBurkholderia pseudomallei

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