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Ayumi Kizawa, Akihito Kawahara, Kosuke Takashima, Yasushi Takimura, Yoshitaka Nishiyama, Yukako Hihara
Specific transcription factors have been identified in various heterotrophic bacterial species that regulate the sets of genes required for fatty acid metabolism. Here, we report that expression of the fab genes, encoding fatty acid biosynthetic enzymes, is regulated by the global regulator LexA in the photoautotrophic cyanobacterium Synechocystis sp. PCC 6803. Sll1626, an ortholog of the well-known LexA repressor involved in the SOS response in heterotrophic bacteria, was isolated from crude extracts of Synechocystis by DNA affinity chromatography, reflecting its binding to the upstream region of the acpP-fabF and fabI genes...
July 26, 2017: Plant Journal: for Cell and Molecular Biology
Alexander G Ekström, Van Kelly, Jon Marles-Wright, Scott L Cockroft, Dominic J Campopiano
We use mass spectrometry analysis and molecular modelling to show the established antimicrobial inhibitor 4,5-dichloro-1,2-dithiol-3-one (HR45) acts by forming a covalent adduct with the target β-ketoacyl-ACP synthase III (FabH). The 5-chloro substituent directs attack of the essential active site thiol (C112) via a Michael-type addition elimination reaction mechanism.
August 2, 2017: Organic & Biomolecular Chemistry
Li Su, Rui Zhang, Kwaku Kyeremeh, Zixin Deng, Hai Deng, Yi Yu
Neocarazostatin A (1) is a potent free radical scavenger possessing an intriguing tricyclic carbazole nucleus with a C4 alkyl side chain attached to ring "A". Although the biosynthetic gene cluster of 1 (nzs) has been identified, and several key steps of the pathway have been well characterized, the enzyme(s) involved in the biosynthesis of the C4 unit still remains obscure. In this work, we demonstrate that three enzymes, including one (MA37-FabG) from primary fatty acid metabolism and two pathway-specific ones (NzsE and NzsF), are responsible for the formation of the side chain precursor...
May 10, 2017: Organic & Biomolecular Chemistry
Junjun Wu, Peng Zhou, Xia Zhang, Mingsheng Dong
Resveratrol has been the subject of numerous scientific investigations due to its health-promoting activities against a variety of diseases. However, developing feasible and efficient microbial processes remains challenging owing to the requirement of supplementing expensive phenylpropanoic precursors. Here, various metabolic engineering strategies were developed for efficient de novo biosynthesis of resveratrol. A recombinant malonate assimilation pathway from Rhizobium trifolii was introduced to increase the supply of the key precursor malonyl-CoA and simultaneously, the clustered regularly interspaced short palindromic repeats interference system was explored to down-regulate fatty acid biosynthesis pathway to inactivate the malonyl-CoA consumption pathway...
July 2017: Journal of Industrial Microbiology & Biotechnology
Yang Zhou, Yu-Shun Yang, Xiao-Da Song, Liang Lu, Hai-Liang Zhu
Fatty acid synthesis (FAS) is an essential metabolism during the whole growth and development process of the bacterial. Several key enzymes which involved in this biosynthetic pathway have been considered as useful targets for the development of new antibacterial agents. Among them, β-ketoacyl-acyl carrier protein synthase III (FabH) is the most magnetic target, since it is central to the initiation of fatty acid biosynthesis and is highly conserved of both Gram-positive and Gram-negative bacteria. Following the previous researches, Schiff-based derivatives with dioxygenated rings and N-heterocycle were synthesized in succession, and their biological activities as potential FabH inhibitors were evaluated in this paper...
2017: Chemical & Pharmaceutical Bulletin
Jeffrey D Rudolf, Liao-Bin Dong, Karina Manoogian, Ben Shen
Platensimycin (PTM) and platencin (PTN) are highly functionalized bacterial diterpenoid natural products that target bacterial and mammalian fatty acid synthases. PTM and PTN feature varying diterpene-derived ketolides that are linked to the same 3-amino-2,4-dihydroxybenzoic acid moiety. As a result, PTM is a selective inhibitor for FabF/FabB, while PTN is a dual inhibitor of FabF/FabB and FabH. We previously determined that the PTM cassette, consisting of five genes found in the ptm, but not ptn, gene cluster, partitions the biosynthesis of the PTM and PTN diterpene-derived ketolides...
December 28, 2016: Journal of the American Chemical Society
Hong-Xia Li, Zhong-Chang Wang, Yu-Mei Qian, Xiao-Qiang Yan, Ya-Dong Lu, Hai-Liang Zhu
New series of chrysin derivatives (4a-4t) were designed and synthesized by introducing different substituted piperazines at C-7 position. Their inhibitory effects on FabH were evaluated using two Gram-negative bacterial strains, Escherichia coli and Pseudomonas aeruginosa, and two Gram-positive bacterial strains, Bacillus subtilis and Staphylococcus aureus. To our delight, most of these compounds exhibited a dramatic increase in inhibitory potency, compared with the control positive drugs. Among them, compound 4s exhibited the most potent inhibitory activity with IC50 values of 5...
January 2017: Chemical Biology & Drug Design
Aaron M Marcella, Adam W Barb
The development of biorenewable chemicals will support green chemistry initiatives and supplement the catalog of starting materials available to the chemical industry. Bacterial fatty acid biosynthesis is being pursued as a source of protein catalysts to synthesize novel reduced carbon molecules in fermentation systems. The availability of methods to measure enzyme catalysis for native and engineered enzymes from this pathway remains a bottleneck because a simple quantitative enzyme assay for numerous enzymes does not exist...
2016: Journal of Biological Methods
David C McKinney, Charles J Eyermann, Rong-Fang Gu, Jun Hu, Steven L Kazmirski, Sushmita D Lahiri, Andrew R McKenzie, Adam B Shapiro, Gloria Breault
Fatty acid biosynthesis is essential to bacterial growth in Gram-negative pathogens. Several small molecules identified through a combination of high-throughput and fragment screening were cocrystallized with FabH (β-ketoacyl-acyl carrier protein synthase III) from Escherichia coli and Streptococcus pneumoniae. Structure-based drug design was used to merge several scaffolds to provide a new class of inhibitors. After optimization for Gram-negative enzyme inhibitory potency, several compounds demonstrated antimicrobial activity against an efflux-negative strain of Haemophilus influenzae...
July 8, 2016: ACS Infectious Diseases
Yong-Hong Yu, Zhe Hu, Hui-Juan Dong, Jin-Cheng Ma, Hai-Hong Wang
Xanthomonas campestris pv. campestris (Xcc), a Gram-negative phytopathogenic bacterium, causes black rot disease of cruciferous vegetables. Although Xcc has a complex fatty acid profile comprised of straight-chain fatty acids and branched-chain fatty acids (BCFAs), and encodes a complete set of genes required for fatty acid synthesis, there is still little known about the mechanism of BCFA synthesis. We reported that expression of Xcc fabH restores the growth of Ralstonia solanacearum fabH mutant, and this allows the R...
2016: Scientific Reports
Katherine A Abrahams, Chun-Wa Chung, Sonja Ghidelli-Disse, Joaquín Rullas, María José Rebollo-López, Sudagar S Gurcha, Jonathan A G Cox, Alfonso Mendoza, Elena Jiménez-Navarro, María Santos Martínez-Martínez, Margarete Neu, Anthony Shillings, Paul Homes, Argyrides Argyrou, Ruth Casanueva, Nicholas J Loman, Patrick J Moynihan, Joël Lelièvre, Carolyn Selenski, Matthew Axtman, Laurent Kremer, Marcus Bantscheff, Iñigo Angulo-Barturen, Mónica Cacho Izquierdo, Nicholas C Cammack, Gerard Drewes, Lluis Ballell, David Barros, Gurdyal S Besra, Robert H Bates
Phenotypic screens for bactericidal compounds are starting to yield promising hits against tuberculosis. In this regard, whole-genome sequencing of spontaneous resistant mutants generated against an indazole sulfonamide (GSK3011724A) identifies several specific single-nucleotide polymorphisms in the essential Mycobacterium tuberculosis β-ketoacyl synthase (kas) A gene. Here, this genomic-based target assignment is confirmed by biochemical assays, chemical proteomics and structural resolution of a KasA-GSK3011724A complex by X-ray crystallography...
September 1, 2016: Nature Communications
Mohammad Sayed Alam, Sefat Jebin, M Mostafizur Rahman, Md Latiful Bari, Dong-Ung Lee
A series of 15 (E)-N'-benzylidenebenzohydrazide analogues were evaluated for their antimicrobial activities against eleven pathogenic and food-borne microbes, namely, S. aureus (G(+)), L. monocytogenes (G(+)), B. subtilis (G(+)), K. pneumonia (G¯), C. sakazakii (G¯), C. freundii (G¯), S. enterica (G¯), S. enteritidis (G¯), E. coli (G¯), Y. pestis (G¯), and P. aeruginosa (G¯). Most of the compounds exhibited selective activity against some Gram-negative bacterial strains. Of the compounds tested (3a-o), 3b and 3g were most active against C...
2016: EXCLI Journal
Natanael D Segretti, Ricardo A M Serafim, Mariana C F Segretti, Marcelo Miyata, Fernando R Coelho, Ohara Augusto, Elizabeth I Ferreira
The development of resistance to antibiotics by microorganisms is a major problem for the treatment of bacterial infections worldwide, and therefore, it is imperative to study new scaffolds that are potentially useful in the development of new antibiotics. In this regard, we propose the design, synthesis and biological evaluation of hybrid sulfonylhydrazone bioisosters/furoxans with potential antibacterial (Escherichia coli) activity. The most active compound of the series, (E)-3-methyl-4-((2-tosylhydrazono)methyl)-1,2,5-oxadiazole 2-oxide, with a MIC=0...
August 15, 2016: Bioorganic & Medicinal Chemistry Letters
Huiya Gu, Robert E Jinkerson, Fiona K Davies, Lyle A Sisson, Philip E Schneider, Matthew C Posewitz
The isolation or engineering of algal cells synthesizing high levels of medium-chain fatty acids (MCFAs) is attractive to mitigate the high clouding point of longer chain fatty acids in algal based biodiesel. To develop a more informed understanding of MCFA synthesis in photosynthetic microorganisms, we isolated several algae from Great Salt Lake and screened this collection for MCFA accumulation to identify strains naturally accumulating high levels of MCFA. A diatom, Chaetoceros sp. GSL56, accumulated particularly high levels of C14 (up to 40%), with the majority of C14 fatty acids allocated in triacylglycerols...
2016: Frontiers in Plant Science
Sarva Santhisudha, Soora Harinath Jayaprakash, Gundluru Mohan, Yellapu Nanda Kumar, Vaithiyanathan Suganthi, Vaithiyalingam Mohanasrinivasan, Cirandur Suresh Reddy
Michael addition of indole derivatives with various substituted nitrostyrenes to yield β- indolylnitroalkanes is accomplished effectively under solvent free conditions using TiO2-SO4(2-) as efficient catalyst at 60 º C. All the synthesized compounds were screened for their antibacterial activity through in silico and in vitro methods. The molecular docking studies against FabH enzyme, a potential drug target of bacterial fatty acid biosynthetic pathway indicated the scope of developing them a new class of antimicrobial agents...
2016: Combinatorial Chemistry & High Throughput Screening
Steffen Lorenz Drees, Chan Li, Fajar Prasetya, Muhammad Saleem, Ingrid Dreveny, Paul Williams, Ulrich Hennecke, Jonas Emsley, Susanne Fetzner
Pseudomonas aeruginosaproduces a number of alkylquinolone-type secondary metabolites best known for their antimicrobial effects and involvement in cell-cell communication. In the alkylquinolone biosynthetic pathway, the β-ketoacyl-(acyl carrier protein) synthase III (FabH)-like enzyme PqsBC catalyzes the condensation of octanoyl-coenzyme A and 2-aminobenzoylacetate (2-ABA) to form the signal molecule 2-heptyl-4(1H)-quinolone. PqsBC, a potential drug target, is unique for its heterodimeric arrangement and an active site different from that of canonical FabH-like enzymes...
March 25, 2016: Journal of Biological Chemistry
Weijia Cao, Weichao Ma, Bowen Zhang, Xin Wang, Kequan Chen, Yan Li, Pingkai Ouyang
The development of efficient microbial processes for pinocembrin production has attracted considerable attention. However, pinocembrin biosynthetic efficiency is greatly limited by the low availability of the malonyl-CoA cofactor in Escherichia coli. Fatty acid biosynthesis is the only metabolic process in E. coli that consumes malonyl-CoA; therefore, we overexpressed the fatty acid biosynthetic pathway enzymes β-ketoacyl-ACP synthase III (FabH) and β-ketoacyl-ACP synthase II (FabF) alone and in combination, and investigated the effect on malonyl-CoA...
April 2016: Journal of Industrial Microbiology & Biotechnology
Kirsten Kuipers, Clement Gallay, Václav Martínek, Manfred Rohde, Markéta Martínková, Samantha L van der Beek, Wouter S P Jong, Hanka Venselaar, Aldert Zomer, Hester Bootsma, Jan-Willem Veening, Marien I de Jonge
Proteins belonging to the DHH family, a member of the phosphoesterase superfamily, are produced by most bacterial species. While some of these proteins are well studied in Bacillus subtilis and Escherichia coli, their functions in Streptococcus pneumoniae remain unclear. Recently, the highly conserved DHH subfamily 1 protein PapP (SP1298) has been reported to play an important role in virulence. Here, we provide a plausible explanation for the attenuated virulence of the papP mutant. Recombinant PapP specifically hydrolyzed nucleotides 3'-phosphoadenosine-5'-phosphate (pAp) and 5'-phosphoadenylyl-(3'->5')-adenosine (pApA)...
July 2016: Molecular Microbiology
Jeffrey D Nanson, Zainab Himiari, Crystall M D Swarbrick, Jade K Forwood
Yersinia pestis, the causative agent of bubonic, pneumonic, and septicaemic plague, remains a major public health threat, with outbreaks of disease occurring in China, Madagascar, and Peru in the last five years. The existence of multidrug resistant Y. pestis and the potential of this bacterium as a bioterrorism agent illustrates the need for new antimicrobials. The β-ketoacyl-acyl carrier protein synthases, FabB, FabF, and FabH, catalyse the elongation of fatty acids as part of the type II fatty acid biosynthesis (FASII) system, to synthesise components of lipoproteins, phospholipids, and lipopolysaccharides essential for bacterial growth and survival...
2015: Scientific Reports
Ruofeng Shang, Jianping Liang, Yunpeng Yi, Yu Liu, Jiatu Wang
Platensimycin and platencin were successively discovered from the strain Streptomyces platensis through systematic screening. These natural products have been defined as promising agents for fighting multidrug resistance in bacteria by targeting type II fatty acid synthesis with slightly different mechanisms. Bioactivity studies have shown that platensimycin and platencin offer great potential to inhibit many resistant bacteria with no cross-resistance or toxicity observed in vivo. This review summarizes the general information on platensimycin and platencin, including antibacterial and self-resistant mechanisms...
2015: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
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