MAC13772
(Synonyms: 2-(2-硝基苯基)硫代乙酮肼) 目录号 : GC38925MAC13772 是 BioA 酶的有效抑制剂 (IC50=250 nM),生物素合成的倒数第二步。MAC13772 是一种新型抗菌化合物。
Cas No.:4871-40-3
Sample solution is provided at 25 µL, 10mM.
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MAC13772 is a potent inhibitor of the enzyme BioA (IC50=250 nM), the antepenultimate step in biotin biosynthesis. MAC13772 is a novel antibacterial compound[1].
[1]. Zlitni S, et al. Metabolic suppression identifies new antibacterial inhibitors under nutrient limitation. Nat Chem Biol. 2013 Dec;9(12):796-804.
Cas No. | 4871-40-3 | SDF | |
别名 | 2-(2-硝基苯基)硫代乙酮肼 | ||
Canonical SMILES | O=C(NN)CSC1=CC=CC=C1[N+]([O-])=O | ||
分子式 | C8H9N3O3S | 分子量 | 227.24 |
溶解度 | DMSO: 17.86 mg/mL (78.60 mM) | 储存条件 | Store at -20°C |
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1 mg | 5 mg | 10 mg | |
1 mM | 4.4006 mL | 22.0032 mL | 44.0063 mL |
5 mM | 0.8801 mL | 4.4006 mL | 8.8013 mL |
10 mM | 0.4401 mL | 2.2003 mL | 4.4006 mL |
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Metabolic suppression identifies new antibacterial inhibitors under nutrient limitation
Nat Chem Biol 2013 Dec;9(12):796-804.PMID:24121552DOI:10.1038/nchembio.1361.
Characterizing new drugs and chemical probes of biological systems is hindered by difficulties in identifying the mechanism of action (MOA) of biologically active molecules. Here we present a metabolite suppression approach to explore the MOA of antibacterial compounds under nutrient restriction. We assembled an array of metabolites that can be screened for suppressors of inhibitory molecules. Further, we identified inhibitors of Escherichia coli growth under nutrient limitation and charted their interactions with our metabolite array. This strategy led to the discovery and characterization of three new antibacterial compounds, MAC168425, MAC173979 and MAC13772. We showed that MAC168425 interferes with glycine metabolism, MAC173979 is a time-dependent inhibitor of p-aminobenzoic acid biosynthesis and MAC13772 inhibits biotin biosynthesis. We conclude that metabolite suppression profiling is an effective approach to focus MOA studies on compounds impairing metabolic capabilities. Such bioactives can serve as chemical probes of bacterial physiology and as leads for antibacterial drug development.
Mimicking the human environment in mice reveals that inhibiting biotin biosynthesis is effective against antibiotic-resistant pathogens
Nat Microbiol 2020 Jan;5(1):93-101.PMID:31659298DOI:10.1038/s41564-019-0595-2.
To revitalize the antibiotic pipeline, it is critical to identify and validate new antimicrobial targets1. In Mycobacteria tuberculosis and Francisella tularensis, biotin biosynthesis is a key fitness determinant during infection2-5, making it a high-priority target. However, biotin biosynthesis has been overlooked for priority pathogens such as Acinetobacter baumannii, Klebsiella pneumoniae and Pseudomonas aeruginosa. This can be attributed to the lack of attenuation observed for biotin biosynthesis genes during transposon mutagenesis studies in mouse infection models6-9. Previous studies did not consider the 40-fold higher concentration of biotin in mouse plasma compared to human plasma. Here, we leveraged the unique affinity of streptavidin to develop a mouse infection model with human levels of biotin. Our model suggests that biotin biosynthesis is essential during infection with A. baumannii, K. pneumoniae and P. aeruginosa. Encouragingly, we establish the capacity of our model to uncover in vivo activity for the biotin biosynthesis inhibitor MAC13772. Our model addresses the disconnect in biotin levels between humans and mice, and explains the failure of potent biotin biosynthesis inhibitors in standard mouse infection models.
The opportunistic pathogen Pseudomonas aeruginosa exploits bacterial biotin synthesis pathway to benefit its infectivity
PLoS Pathog 2023 Jan 23;19(1):e1011110.PMID:36689471DOI:10.1371/journal.ppat.1011110.
Pseudomonas aeruginosa is an opportunistic pathogen that predominantly causes nosocomial and community-acquired lung infections. As a member of ESKAPE pathogens, carbapenem-resistant P. aeruginosa (CRPA) compromises the limited therapeutic options, raising an urgent demand for the development of lead compounds against previously-unrecognized drug targets. Biotin is an important cofactor, of which the de novo synthesis is an attractive antimicrobial target in certain recalcitrant infections. Here we report genetic and biochemical definition of P. aeruginosa BioH (PA0502) that functions as a gatekeeper enzyme allowing the product pimeloyl-ACP to exit from fatty acid synthesis cycle and to enter the late stage of biotin synthesis pathway. In relative to Escherichia coli, P. aeruginosa physiologically requires 3-fold higher level of cytosolic biotin, which can be attributed to the occurrence of multiple biotinylated enzymes. The BioH protein enables the in vitro reconstitution of biotin synthesis. The repertoire of biotin abundance is assigned to different mouse tissues and/or organ contents, and the plasma biotin level of mouse is around 6-fold higher than that of human. Removal of bioH renders P. aeruginosa biotin auxotrophic and impairs its intra-phagosome persistence. Based on a model of CD-1 mice mimicking the human environment, lung challenge combined with systemic infection suggested that BioH is necessary for the full virulence of P. aeruginosa. As expected, the biotin synthesis inhibitor MAC13772 is capable of dampening the viability of CRPA. Notably, MAC13772 interferes the production of pyocyanin, an important virulence factor of P. aeruginosa. Our data expands our understanding of P. aeruginosa biotin synthesis relevant to bacterial infectivity. In particular, this study represents the first example of an extracellular pathogen P. aeruginosa that exploits biotin cofactor as a fitness determinant, raising the possibility of biotin synthesis as an anti-CRPA target.