Antibacterial targets in fatty acid biosynthesis

Wright, H.T.; Reynolds, Kevin A.

doi:10.1016/j.mib.2007.07.001

Cited by 171 publications

(99 citation statements)

References 30 publications

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“…The importance of the fatty acid biosynthesis pathway makes the FAS systems attractive targets for the development of compounds with antibiotic or antitumor properties (3)(4)(5). This potential is further underlined by the potency of the classic drugs isoniazid and triclosan, both inhibiting the ER step of bacterial fatty acid biosynthesis (6,7).…”

mentioning

confidence: 99%

Inhibition of the fungal fatty acid synthase type I multienzyme complex

Johansson

Wiltschi

Kumari

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

118

134

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Fatty acids are among the major building blocks of living cells, making lipid biosynthesis a potent target for compounds with antibiotic or antineoplastic properties. We present the crystal structure of the 2.6-MDa Saccharomyces cerevisiae fatty acid synthase (FAS) multienzyme in complex with the antibiotic cerulenin, representing, to our knowledge, the first structure of an inhibited fatty acid megasynthase. Cerulenin attacks the FAS ketoacyl synthase (KS) domain, forming a covalent bond to the active site cysteine C1305. The inhibitor binding causes two significant conformational changes of the enzyme. First, phenylalanine F1646, shielding the active site, flips and allows access to the nucleophilic cysteine. Second, methionine M1251, placed in the center of the acyl-binding tunnel, rotates and unlocks the inner part of the fatty acid binding cavity. The importance of the rotational movement of the gatekeeping M1251 side chain is reflected by the cerulenin resistance and the changed product spectrum reported for S. cerevisiae strains mutated in the adjacent glycine G1250. Platensimycin and thiolactomycin are two other potent inhibitors of KSs. However, in contrast to cerulenin, they show selectivity toward the prokaryotic FAS system. Because the flipped F1646 characterizes the catalytic state accessible for platensimycin and thiolactomycin binding, we superimposed structures of inhibited bacterial enzymes onto the S. cerevisiae FAS model. Although almost all side chains involved in inhibitor binding are conserved in the FAS multienzyme, a different conformation of the loop K1413-K1423 of the KS domain might explain the observed low antifungal properties of platensimycin and thiolactomycin.cerulenin ͉ platensimycin ͉ thiolactomycin ͉ fatty acid synthesis ͉ yeast T hree different schemes for de novo synthesis of fatty acids are found in nature. Eukaryotes and advanced prokaryotes generally use the type I fatty acid synthase system (FAS I), composed of complexes of large multifunctional enzymes. Bacteria, in contrast, use the dissociated FAS II system that consists of a set of separate enzymes, each catalyzing one of the reactions of the fatty acid synthase cycle (1). A third system exists in some parasites that use membrane-bound fatty acid elongases for the synthesis of aliphatic chains (2). Despite this considerable variation, the individual reaction steps of fatty acid biosynthesis are essentially conserved in all kingdoms of life. Four basic reactions constitute a single round of elongation. In the first step, an acceptor CoA or acyl carrier protein (ACP) associated acetyl unit is condensed with malonyl-ACP to form ␤-ketobutyryl-ACP, which is subsequently reduced by an NADPH-dependent ketoacyl-ACP reductase. The resulting ␤-hydroxyacyl-ACP is dehydrated to produce enoyl-ACP and finally reduced by an enoyl reductase (ER) to form the saturated acyl-ACP, which can be further elongated in a new cycle [see supporting information (SI) Fig. S1].The importance of the fatty acid biosynthesis pathway makes the FAS sys...

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mentioning

confidence: 99%

Inhibition of the fungal fatty acid synthase type I multienzyme complex

Johansson

Wiltschi

Kumari

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

118

134

View full text Add to dashboard Cite

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“…To this end, we established a reference compendium of proteome response profiles for over 40 antibiotics, including almost all clinically relevant antibiotic classes. Recently, the discovery of novel inhibitors with antibacterial activity sparked renewed interest in fatty acid biosynthesis as an antibiotic target (34). The comparison of proteomic responses to four different inhibitors of fatty acid biosynthesis allowed the description of a proteomic signature diagnostic of fatty acid biosynthesis inhibition consisting of six upregulated proteins connected to the target pathway.…”

Section: Discussionmentioning

confidence: 99%

Proteomic Signature of Fatty Acid Biosynthesis Inhibition Available for In Vivo Mechanism-of-Action Studies

Wenzel

Patra

Albrecht

et al. 2011

Antimicrob Agents Chemother

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Fatty acid biosynthesis is a promising novel antibiotic target. Two inhibitors of fatty acid biosynthesis, platencin and platensimycin, were recently discovered and their molecular targets identified. Numerous structure-activity relationship studies for both platencin and platensimycin are currently being undertaken. We established a proteomic signature for fatty acid biosynthesis inhibition in Bacillus subtilis using platencin, platensimycin, cerulenin, and triclosan. The induced proteins, FabHA, FabHB, FabF, FabI, PlsX, and PanB, are enzymes involved in fatty acid biosynthesis and thus linked directly to the target pathway. The proteomic signature can now be used to assess the in vivo mechanisms of action of compounds derived from structureactivity relationship programs, as demonstrated for the platensimycin-inspired chromium bioorganometallic PM47. It will further serve as a reference signature for structurally novel natural and synthetic antimicrobial compounds with unknown mechanisms of action. In summary, we described a proteomic signature in B. subtilis consisting of six upregulated proteins that is diagnostic of fatty acid biosynthesis inhibition and thus can be applied to advance antibacterial drug discovery programs.

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“…Specifically, the mechanisms that permit the bacteria to survive and adapt to niche microenvironments inside host cells will need to be delineated (Eisenreich et al, 2010). In contrast, ACC has been the subject of greater research focus primarily due to its potential as an antibiotic drug target (Wright and Reynolds, 2007;Chan and Vogel, 2010;Parsons and Rock, 2011). ACC catalyses the carboxylation of various acyl CoA substrates, such as acetyl CoA, propionyl CoA and butyryl CoA (Arabolaza et al, 2010;Gago et al, 2011).…”

Section: Biotin Is An Enzyme Cofactormentioning

confidence: 99%