MINI-REVIEWS IN MEDICINAL CHEMISTRY
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2023
·Vol. 23
·期 3
·343-360
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IF 3.8
Palathoti Nagarjuna,Azam Mohammed A.
Bacterial infections are a major cause of mortality and morbidity in humans throughout the world. Infections due to resistant bacterial strains such as methicillin-resistant Staphyloccocusaureus vancomycin, resistant Enterococci, Klebsiella pneumoniae, Staphylococcus aureus, and Mycobacterium
are alarming. Hence the development of new antibacterial agents, which act via a novel mechanism of action, became a priority in antibacterial research. One such approach to overcome bacterial resistance is to target novel protein and develop antibacterial agents that act via different mechanisms
of action. Bacterial GlmU is one such bifunctional enzyme that catalyzes the two consecutive reactions during the biosynthesis of uridine 5′-diphospho-Nacetylglucosamine, an essential precursor for the biosynthesis of bacterial cell wall peptidoglycan. This enzyme comprises two distinct
active sites; acetyltransferase and uridyltransferase and both these active sites act independently during catalytic reactions. GlmU is considered an attractive target for the design and development of newer antibacterial agents due to its important role in bacterial cell wall synthesis and
the absence of comparable enzymes in humans. Availability of three dimensions X-crystallographic structures of GlmU and their known catalytic mechanism from different bacterial strains have instigated research efforts for the development of novel antibacterial agents. Several GlmU inhibitors
belonging to different chemical classes like 2- phenylbenzofuran derivative, quinazolines, aminoquinazolines, sulfonamides, arylsulfonamide, D-glucopyranoside 6-phosphates, terreic acid, iodoacetamide, N-ethyl maleimide, and Nethylmaleimide etc., have been reported in the literature. In the
present review, we present an update on GlmU inhibitors and their associated antibacterial activities. This review may be useful for the design and development of novel GlmU inhibitors with potent antibacterial activity.
研究领域:
微生物学
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药物化学
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生物化学
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DOI
PubMed
高影响因子
Frontiers in Cellular and Infection Microbiology
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2019
·
IF 3.518
Chen Changming,Han Xiuyan,Yan Qiulong,Wang Chao,Jia Liqiu,Taj Ayaz,Zhao Lizhe,Ma Yufang
Mycobacterium tuberculosis bifunctional enzyme GlmU is a novel target for anti-TB drugs and is involved in glycosyl donor UDP-N-acetylglucosamine biosynthesis. Here, we found that TPSA (2-[5-(2-{[4-(2-thienyl)-2-pyrimidinyl]sulfanyl}acetyl)-2-thienyl]acetic acid) was a novel inhibitor for GlmU acetyltransferase activity (IC50: 5.3 μM). The interaction sites of GlmU and TPSA by molecular docking were confirmed by site-directed mutagenesis. TPSA showed an inhibitory effect on Mtb H37Ra growth and intracellular H37Ra in macrophage cells (MIC: 66.5 μM). To investigate why TPSA at a higher concentration (66.5 μM) was able to inhibit H37Ra growth, proteome and transcriptome of H37Ra treated with TPSA were analyzed. The expression of two methyltransferases MRA_0565 (Rv0558) and MRA_0567 (Rv0560c) were markedly increased. TPSA was pre-incubated with purified Rv0558 and Rv0560c in the presence of S-adenosylmethionine (methyl donor) respectively, resulting in its decreased inhibitory effect of GlmU on acetyltransferase activity. The inhibition of TPSA on growth of H37Ra with overexpressed Rv0558 and Rv0560c was reduced. These implied that methyltransferases could modify TPSA. The methylation of TPSA catalyzed by Rv0560c was subsequently confirmed by LC-MS. Therefore, TPSA as a GlmU acetyltransferase activity inhibitor may offer a structural basis for new anti-tuberculosis drugs. TPSA needs to be modified further by some groups to prevent its methylation by methyltransferases.
研究领域:
微生物学
·
药理学
·
分子生物学
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DOI
PubMed
高影响因子
Frontiers in Microbiology
·
2019
·
IF 4.259
Han Xiuyan,Chen Changming,Yan Qiulong,Jia Liqiu,Taj Ayaz,Ma Yufang
Mycobacterium tuberculosis is one of most pathogenic microorganisms in the world. Previously, the bifunctional enzyme GlmU with glucosamine-1-phosphate acetyltransferase activity and N-acetylglucosamine-1-phosphate uridyltransferase activity has been suggested as a potential drug target; therefore, discovering compounds targeting GlmU acetyltransferase is necessary. The natural products were tested for inhibition of GlmU acetyltransferase activity. We found that dicumarol exhibited inhibitory effects on GlmU acetyltransferase, with a concentration achieving a 50% inhibition (IC50) value of 4.608 μg/ml (13.7 μM). The inhibition kinetics indicated that dicumarol uncompetitively inhibited acetyl CoA and showed mixed-type inhibition for glucosamine-1-phosphate (GlcN-1-P). The activity of dicumarol against M. tuberculosis H37Ra was evaluated with a minimum inhibitory concentration (MIC) value of 6.25 μg/ml (18.55 μM) in the Alamar blue assay. Dicumarol also exhibited inhibitory effects on several clinically sensitive M. tuberculosis strains and drug-resistant strains, with a range of MIC value of 6.25 to >100 μg/ml. Dicumarol increased the sensitivity of anti-tuberculosis drugs (isoniazid and rifampicin) when dicumarol was present at a low concentration. The transcriptome and proteome data of M. tuberculosis H37Ra treated by dicumarol showed that the affected genes were associated with cell wall synthesis, DNA damage and repair, metabolic processes, and signal transduction. These results provided the mechanism of dicumarol inhibition against GlmU acetyltransferase and M. tuberculosis and also suggested that dicumarol is a potential candidate for TB treatment.
研究领域:
微生物学
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药理学
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分子生物学
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结核病研究
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产品关联
DOI
PubMed
高影响因子
Science Advances
·
2023
·Vol. 9
·期 31
·
IF 13.6
Jia Jia,Mingxin Zheng,Chongwen Zhang,Binglei Li,Cai Lu,Yuefan Bai,Qian Tong,Xudong Hang,Yixin Ge,Liping Zeng,Ming Zhao,Fuhang Song,Huawei Zhang,Liang Zhang,Kui Hong,Hongkai Bi
Staphylococcus aureus poses a severe public health problem as one of the vital causative agents of healthcare- and community-acquired infections. There is a globally urgent need for new drugs with a novel mode of action (MoA) to combat S. aureus biofilms and persisters that tolerate antibiotic treatment. We demonstrate that a benzonaphthopyranone glycoside, chrysomycin A (ChryA), is a rapid bactericide that is highly active against S. aureus persisters, robustly eradicates biofilms in vitro, and shows a sustainable killing efficacy in vivo. ChryA was suggested to target multiple critical cellular processes. A wide range of genetic and biochemical approaches showed that ChryA directly binds to GlmU and DapD, involved in the biosynthetic pathways for the cell wall peptidoglycan and lysine precursors, respectively, and inhibits the acetyltransferase activities by competition with their mutual substrate acetyl-CoA. Our study provides an effective antimicrobial strategy combining multiple MoAs onto a single small molecule for treatments of S. aureus persistent infections.
研究领域:
微生物学
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药理学
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传染病学
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分子生物学
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DOI
PubMed
高影响因子
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