MraY Inhibitors as Novel Antibacterial Agents

Dini, C.

doi:10.2174/156802605774463042

Cited by 102 publications

(60 citation statements)

References 42 publications

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“…The mode of action of these liponucleosides is inhibition of peptidoglycan synthesis by inhibition of phospho‐MurNAc‐pentapeptide translocase (MraY translocase I). MraY is essential for bacterial cell growth, thus making it a target of interest for the treatment of tuberculosis (TB),100 and even vancomycin‐ and methicillin‐resistant Staphylococcus aureus (VRSA, MRSA) 101…”

Section: Natural Product Derived Fragments In Drug Discoverymentioning

confidence: 99%

Capturing Biological Activity in Natural Product Fragments by Chemical Synthesis

2016

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Natural products have had an immense influence on science and have directly led to the introduction of many drugs. Organic chemistry, and its unique ability to tailor natural products through synthesis, provides an extraordinary approach to unlock the full potential of natural products. In this Review, an approach based on natural product derived fragments is presented that can successfully address some of the current challenges in drug discovery. These fragments often display significantly reduced molecular weights, reduced structural complexity, a reduced number of synthetic steps, while retaining or even improving key biological parameters such as potency or selectivity. Examples from various stages of the drug development process up to the clinic are presented. In addition, this process can be leveraged by recent developments such as genome mining, antibody–drug conjugates, and computational approaches. All these concepts have the potential to identify the next generation of drug candidates inspired by natural products.

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Section: Natural Product Derived Fragments In Drug Discoverymentioning

confidence: 99%

Capturing Biological Activity in Natural Product Fragments by Chemical Synthesis

2016

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“…2.7.8.13), an integral membrane protein. 3 Several natural product inhibitors of this enzyme have been discovered that have antibacterial activity, 4,5 such as mureidomycin, liposidomycin, capuramycin, and muraymycin, validating MraY as a target for antibacterial drugs. None of these natural product inhibitors has reached clinical practice in humans, however.…”

Section: Introductionmentioning

confidence: 99%

A High-Throughput, Homogeneous, Fluorescence Resonance Energy Transfer-Based Assay for Phospho-N-acetylmuramoyl-pentapeptide Translocase (MraY)

et al. 2012

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Peptidoglycan biosynthesis is an essential process in bacteria and is therefore a suitable target for the discovery of new antibacterial drugs. One of the last cytoplasmic steps of peptidoglycan biosynthesis is catalyzed by the integral membrane protein MraY, which attaches soluble UDP-N-acetylmuramoyl-pentapeptide to the membrane-bound acceptor undecaprenyl phosphate. Although several natural product-derived inhibitors of MraY are known, none have the properties necessary to be of clinical use as antibacterial drugs. Here we describe a novel, homogeneous, fluorescence resonance energy transferbased MraY assay that is suitable for high-throughput screening for novel MraY inhibitors. The assay allows for continuous measurement, or it can be quenched prior to measurement.

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“…The question is why no inhibitor has yet come into clinical use after so many years of effort. Some of the reasons for this were recently discussed (57). The successful study of the catalytic mechanism of MurG illustrates quite well the advantages of combining biochemical and structural approaches.…”

Section: Discussionmentioning

confidence: 94%

“…Although MraY was successfully purified (25), its structural study is a difficult challenge owing to its 10-segment transmembrane topology but remains a necessity, considering the potency of its numerous known inhibitors (57). The question is why no inhibitor has yet come into clinical use after so many years of effort.…”

Section: Discussionmentioning

confidence: 99%

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Lipid Intermediates in the Biosynthesis of Bacterial Peptidoglycan

Heijenoort

2007

Microbiol Mol Biol Rev

173

135

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SUMMARY This review is an attempt to bring together and critically evaluate the now-abundant but dispersed data concerning the lipid intermediates of the biosynthesis of bacterial peptidoglycan. Lipid I, lipid II, and their modified forms play a key role not only as the specific link between the intracellular synthesis of the peptidoglycan monomer unit and the extracytoplasmic polymerization reactions but also in the attachment of proteins to the bacterial cell wall and in the mechanisms of action of antibiotics with which they form specific complexes. The survey deals first with their detection, purification, structure, and preparation by chemical and enzymatic methods. The recent important advances in the study of transferases MraY and MurG, responsible for the formation of lipids I and II, are reported. Various modifications undergone by lipids I and II are described, especially those occurring in gram-positive organisms. The following section concerns the cellular location of the lipid intermediates and the translocation of lipid II across the cytoplasmic membrane. The great efforts made since 2000 in the study of the glycosyltransferases catalyzing the glycan chain formation with lipid II or analogues are analyzed in detail. Finally, examples of antibiotics forming complexes with the lipid intermediates are presented.

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MraY Inhibitors as Novel Antibacterial Agents

Cited by 102 publications

References 42 publications

Capturing Biological Activity in Natural Product Fragments by Chemical Synthesis

Capturing Biological Activity in Natural Product Fragments by Chemical Synthesis

A High-Throughput, Homogeneous, Fluorescence Resonance Energy Transfer-Based Assay for Phospho-N-acetylmuramoyl-pentapeptide Translocase (MraY)

Lipid Intermediates in the Biosynthesis of Bacterial Peptidoglycan

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