Crystal Structure of Carboxyltransferase from <i>Staphylococcus aureus</i> Bound to the Antibacterial Agent Moiramide B

Silvers, Molly A.; Pakhomova, Svetlana; Neau, David; Silvers, William; Anzalone, Nicholas; Taylor, Carol M.; Waldrop, Grover L.

doi:10.1021/acs.biochem.6b00641

Cited by 19 publications

(19 citation statements)

References 36 publications

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“…The conserved primary sequence and structure near the active site makes this enzyme attractive for developing new antibiotics. A few other compounds do inhibit bacterial ACCs (36)(37)(38)(39)(40), but the structure of thailandamide is different from those inhibitors. Further analysis of AccA and thailandamide may identify a path to a clinically useful drug.…”

Section: Discussionmentioning

confidence: 99%

Thailandamide, a Fatty Acid Synthesis Antibiotic That Is Coexpressed with a Resistant Target Gene

Wozniak

Lin

Schmidt

et al. 2018

Antimicrob Agents Chemother

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Microbes encode many uncharacterized gene clusters that may produce antibiotics and other bioactive small molecules. Methods for activating these genes are needed to explore their biosynthetic potential. A transposon containing an inducible promoter was randomly inserted into the genome of the soil bacterium to induce antibiotic expression. This screen identified the polyketide/nonribosomal peptide thailandamide as an antibiotic and discovered its regulator, AtsR. Mutants of resistant to thailandamide had mutations in the gene for acetyl coenzyme A (acetyl-CoA) carboxylase, which is one of the first enzymes in the fatty acid synthesis pathway. A second copy of in the thailandamide synthesis gene cluster keeps resistant to its own antibiotic. These genetic techniques will likely be powerful tools for discovering other unusual antibiotics.

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Section: Discussionmentioning

confidence: 99%

Thailandamide, a Fatty Acid Synthesis Antibiotic That Is Coexpressed with a Resistant Target Gene

Wozniak

Lin

Schmidt

et al. 2018

Antimicrob Agents Chemother

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“…Several selective compounds exist that target only the eukaryotic ACC [36]. Among the drugs targeting bacterial ACC, several are natural products, including thailandamide B, andrimid, and moiramide B [36][37][38][39]. Mutational analysis of Salmonella enterica ACC resistant to thailandamide B revealed a series of residues in the beta protein adjacent to the interface between the alpha and beta subunits [37,38].…”

Section: Plos Onementioning

confidence: 99%

“…Mutational analysis of Salmonella enterica ACC resistant to thailandamide B revealed a series of residues in the beta protein adjacent to the interface between the alpha and beta subunits [37,38]. A crystal structure of moiramide B bound to the S. aureus ACC demonstrated that inhibition occurs at the interface between the alpha and beta subunits [39], which is nearby but not identical to the binding site proposed for thailandamide B.…”

Section: Plos Onementioning

confidence: 99%

“…Thus, we hypothesize that in tetramic acids, the pyrrolidinedione warhead could bind in the same place as in the moiramide B series. Alternatively, it is known that there is a zinc cation in the S. aureus ACC [39,42]; perhaps metal chelation is again important in this instance. Further research is required to determine the exact molecular interactions by which EQI and PYRC inhibit ACC.…”

Section: Plos Onementioning

confidence: 99%

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Pyrrolocin C and equisetin inhibit bacterial acetyl-CoA carboxylase

et al. 2020

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Antimicrobial resistance is a growing global health and economic concern. Current antimicrobial agents are becoming less effective against common bacterial infections. We previously identified pyrrolocins A and C, which showed activity against a variety of Grampositive bacteria. Structurally similar compounds, known as pyrrolidinediones (e.g., TA-289, equisetin), also display antibacterial activity. However, the mechanism of action of these compounds against bacteria was undetermined. Here, we show that pyrrolocin C and equisetin inhibit bacterial acetyl-CoA carboxylase (ACC), the first step in fatty acid synthesis. We used transcriptomic data, metabolomic analysis, fatty acid rescue and acetate incorporation experiments to show that a major mechanism of action of the pyrrolidinediones is inhibition of fatty acid biosynthesis, identifying ACC as the probable molecular target. This hypothesis was further supported using purified proteins, demonstrating that biotin carboxylase is the inhibited component of ACC. There are few known antibiotics that target this pathway and, therefore, we believe that these compounds may provide the basis for alternatives to current antimicrobial therapy.

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“…Since malonyl-CoA synthesis is the essential first step in fatty acid and phospholipid biosynthesis, it is likely that this mutation can be intrinsically suppressed and thus does not result in a complete loss of AccA synthesis. The accA mutation isolated in the Δdac yfkC* mutant results in an A229V substitution in the active site of the enzyme [66,67] (see S5 Fig.). For AccC, the mutation (H298Y) is located in the highly conserved active site motif of the enzyme (S5 Fig).…”

Section: A Reduction Of Phospholipid Biosynthesis Helps To Overcome Tmentioning

confidence: 99%

Essentiality of c-di-AMP inBacillus subtilis: Bypassing mutations converge in potassium and glutamate homeostasis

Krüger

Herzberg

Rath

et al. 2020

Preprint

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In order to adjust to changing environmental conditions, bacteria use nucleotide second messengers to transduce external signals and translate them into a specific cellular response. Cyclic di-adenosine monophosphate (c-di-AMP) is the only known essential nucleotide second messenger. In addition to the well-established role of this second messenger in the control of potassium homeostasis, we observed that glutamate is as toxic as potassium for a c-di-AMP-free strain of the Gram-positive model bacterium Bacillus subtilis . In this work, we isolated suppressor mutants that allow growth of a c-di-AMP-free strain under these toxic conditions. Characterization of glutamate resistant suppressors revealed that they contain pairs of mutations, in most cases affecting glutamate and potassium homeostasis. Among these mutations, several independent mutations affected a novel glutamate transporter, AimA ( A mino acid im porter A , formerly YbeC). This protein is the major transporter for glutamate and serine in B. subtilis . Unexpectedly, some of the isolated suppressor mutants could suppress glutamate toxicity by a combination of mutations that affect phospholipid biosynthesis and a specific gain-of-function mutation of a mechanosensitive channel of small conductance (YfkC) suggesting the acquisition of a device for glutamate export. Cultivation of the c-di-AMP-free strain on complex medium was an even greater challenge because the amounts of potassium, glutamate, and other osmolytes are substantially higher than in minimal medium. Suppressor mutants viable on complex medium could only be isolated under anaerobic conditions if one of the two c-di-AMP receptor proteins, DarA or DarB, was absent. Also on complex medium, potassium and osmolyte toxicity are the major bottlenecks for the growth of B. subtilis in the absence of c-di-AMP. Our results indicate that the essentiality of c-di-AMP in B. subtilis is caused by the global impact of the second messenger nucleotide on different aspects of cellular physiology.

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

Cited by 19 publications

References 36 publications

Thailandamide, a Fatty Acid Synthesis Antibiotic That Is Coexpressed with a Resistant Target Gene

Thailandamide, a Fatty Acid Synthesis Antibiotic That Is Coexpressed with a Resistant Target Gene

Pyrrolocin C and equisetin inhibit bacterial acetyl-CoA carboxylase

Essentiality of c-di-AMP inBacillus subtilis: Bypassing mutations converge in potassium and glutamate homeostasis

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