Bacterial &amp;#946;-Ketoacyl-Acyl Carrier Protein Synthase III (FabH): An Attractive Target for the Design of New Broad-Spectrum Antimicrobial Agents

Castillo, Yunierkis P.; Cabrera‐Pérez, Miguel Ángel

doi:10.2174/138955708783331559

Cited by 19 publications

(4 citation statements)

References 33 publications

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“…FabH, which encodes 3-oxoacyl-(acyl-carrier-protein) synthase, is essential in the absence of long chain fatty acids in some species, such as E. coli , but not in others, such as Pseudomonas aeruginosa [30], [31], and has been identified as a promising drug target in pathogenic bacteria [32]. The B. thailandensis FabH gene (BTH_I1717) was among the group of genes we identified as essential for in vitro growth using rich medium.…”

Section: Resultsmentioning

confidence: 99%

Combining Functional and Structural Genomics to Sample the Essential Burkholderia Structome

et al. 2013

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BackgroundThe genus Burkholderia includes pathogenic gram-negative bacteria that cause melioidosis, glanders, and pulmonary infections of patients with cancer and cystic fibrosis. Drug resistance has made development of new antimicrobials critical. Many approaches to discovering new antimicrobials, such as structure-based drug design and whole cell phenotypic screens followed by lead refinement, require high-resolution structures of proteins essential to the parasite.Methodology/Principal FindingsWe experimentally identified 406 putative essential genes in B. thailandensis, a low-virulence species phylogenetically similar to B. pseudomallei, the causative agent of melioidosis, using saturation-level transposon mutagenesis and next-generation sequencing (Tn-seq). We selected 315 protein products of these genes based on structure-determination criteria, such as excluding very large and/or integral membrane proteins, and entered them into the Seattle Structural Genomics Center for Infection Disease (SSGCID) structure determination pipeline. To maximize structural coverage of these targets, we applied an “ortholog rescue” strategy for those producing insoluble or difficult to crystallize proteins, resulting in the addition of 387 orthologs (or paralogs) from seven other Burkholderia species into the SSGCID pipeline. This structural genomics approach yielded structures from 31 putative essential targets from B. thailandensis, and 25 orthologs from other Burkholderia species, yielding an overall structural coverage for 49 of the 406 essential gene families, with a total of 88 depositions into the Protein Data Bank. Of these, 25 proteins have properties of a potential antimicrobial drug target i.e., no close human homolog, part of an essential metabolic pathway, and a deep binding pocket. We describe the structures of several potential drug targets in detail.Conclusions/SignificanceThis collection of structures, solubility and experimental essentiality data provides a resource for development of drugs against infections and diseases caused by Burkholderia. All expression clones and proteins created in this study are freely available by request.

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Section: Resultsmentioning

confidence: 99%

Combining Functional and Structural Genomics to Sample the Essential Burkholderia Structome

et al. 2013

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“…FabH, also known as β-ketoacyl-(acyl-carrier-protein)synthase III (KAS III), is a key enzyme involved in the biosynthesis of bacterial fatty acids, being responsible for the first condensation reaction between acetyl-coA and malonyl-acyl carrier protein (ACP), with the formation of acetoacetyl-ACP. FabH is found in many bacterial pathogens including Escherichia coli, Staphylococcus aureus, Mycobacterium tuberculosis, Enterococcus faecium, Streptococcus pneumoniae, Pseudomonas aeruginosa, Neisseria meningitidis, and Haemophilus influenzae, most of them possessing high levels of resistance to currently authorized antimicrobial drugs [56]. The three-dimensional structure of the FabH protein is well preserved among many Gram-positive and Gram-negative bacteria.…”

Section: Antimicrobial Activitymentioning

confidence: 99%

An Overview of the Synthesis and Antimicrobial, Antiprotozoal, and Antitumor Activity of Thiazole and Bisthiazole Derivatives

et al. 2021

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Thiazole, a five-membered heteroaromatic ring, is an important scaffold of a large number of synthetic compounds. Its diverse pharmacological activity is reflected in many clinically approved thiazole-containing molecules, with an extensive range of biological activities, such as antibacterial, antifungal, antiviral, antihelmintic, antitumor, and anti-inflammatory effects. Due to its significance in the field of medicinal chemistry, numerous biologically active thiazole and bisthiazole derivatives have been reported in the scientific literature. The current review provides an overview of different methods for the synthesis of thiazole and bisthiazole derivatives and describes various compounds bearing a thiazole and bisthiazole moiety possessing antibacterial, antifungal, antiprotozoal, and antitumor activity, encouraging further research on the discovery of thiazole-containing drugs.

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“…Our results suggest that HOS2 and other histone deacetylases (such as RPD3) are potential antifungal drug targets [ 86 , 87 , 88 ]. Additionally, FABH is an essential enzyme for the synthesis of fatty acids in bacteria, and it has been investigated for its potential as a drug target [ 89 ]. In the specific case of S. aureus , FABH has been validated as a target of many chemical compounds presenting antibacterial activity [ 90 , 91 , 92 , 93 ].…”

Section: Discussionmentioning

confidence: 99%

Synthetic Cinnamides and Cinnamates: Antimicrobial Activity, Mechanism of Action, and In Silico Study

et al. 2023

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The severity of infectious diseases associated with the resistance of microorganisms to drugs highlights the importance of investigating bioactive compounds with antimicrobial potential. Therefore, nineteen synthetic cinnamides and cinnamates having a cinnamoyl nucleus were prepared and submitted for the evaluation of antimicrobial activity against pathogenic fungi and bacteria in this study. To determine the minimum inhibitory concentration (MIC) of the compounds, possible mechanisms of antifungal action, and synergistic effects, microdilution testing in broth was used. The structures of the synthesized products were characterized with FTIR spectroscopy, 1 H-NMR, 13 C-NMR, and HRMS. Derivative 6 presented the best antifungal profile, suggesting that the presence of the butyl substituent potentiates its biological response (MIC = 626.62 μM), followed by compound 4 (672.83 μM) and compound 3 (726.36 μM). All three compounds were fungicidal, with MFC/MIC ≤ 4. For mechanism of action, compounds 4 and 6 directly interacted with the ergosterol present in the fungal plasmatic membrane and with the cell wall. Compound 18 presented the best antibacterial profile (MIC = 458.15 μM), followed by compound 9 (550.96 μM) and compound 6 (626.62 μM), which suggested that the presence of an isopropyl group is important for antibacterial activity. The compounds were bactericidal, with MBC/MIC ≤ 4. Association tests were performed using the Checkerboard method to evaluate potential synergistic effects with nystatin (fungi) and amoxicillin (bacteria). Derivatives 6 and 18 presented additive effects. Molecular docking simulations suggested that the most likely targets of compound 6 in C. albicans were caHOS2 and caRPD3, while the most likely target of compound 18 in S. aureus was saFABH. Our results suggest that these compounds could be used as prototypes to obtain new antimicrobial drugs.

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Bacterial β-Ketoacyl-Acyl Carrier Protein Synthase III (FabH): An Attractive Target for the Design of New Broad-Spectrum Antimicrobial Agents

Cited by 19 publications

References 33 publications

Combining Functional and Structural Genomics to Sample the Essential Burkholderia Structome

Combining Functional and Structural Genomics to Sample the Essential Burkholderia Structome

An Overview of the Synthesis and Antimicrobial, Antiprotozoal, and Antitumor Activity of Thiazole and Bisthiazole Derivatives

Synthetic Cinnamides and Cinnamates: Antimicrobial Activity, Mechanism of Action, and In Silico Study

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