Small molecule inhibitors of peptidoglycan synthesis targeting the lipid II precursor

Derouaux, Adeline; Turk, Samo; Olrichs, Nick K.; Gobec, Stanislav; Breukink, Eefjan; Amoroso, Ana Maria; Offant, Julien; Bostock, Julieanne M.; Mariner, Katherine R.; Chopra, Ian; Vernet, Thierry; Zervosen, Astrid; Joris, Bernard; Frère, Jean‐Marie; Nguyen-Distèche, Martine; Terrak, Mohammed

doi:10.1016/j.bcp.2011.02.008

Cited by 21 publications

(30 citation statements)

References 48 publications

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“…Hence, blocking bacterial cell wall synthesis is a widely deployed innate defense mechanism. It is possible to identify small molecule mimetics that bind bacterial cell walls [253,254]. Although not discussed here, other defensins can directly recognize specific lipids in fungal membranes [255,256,257].…”

Section: Mechanism Of Action Of Human Antimicrobial Peptidesmentioning

confidence: 99%

Human Antimicrobial Peptides and Proteins

2014

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As the key components of innate immunity, human host defense antimicrobial peptides and proteins (AMPs) play a critical role in warding off invading microbial pathogens. In addition, AMPs can possess other biological functions such as apoptosis, wound healing, and immune modulation. This article provides an overview on the identification, activity, 3D structure, and mechanism of action of human AMPs selected from the antimicrobial peptide database. Over 100 such peptides have been identified from a variety of tissues and epithelial surfaces, including skin, eyes, ears, mouths, gut, immune, nervous and urinary systems. These peptides vary from 10 to 150 amino acids with a net charge between −3 and +20 and a hydrophobic content below 60%. The sequence diversity enables human AMPs to adopt various 3D structures and to attack pathogens by different mechanisms. While α-defensin HD-6 can self-assemble on the bacterial surface into nanonets to entangle bacteria, both HNP-1 and β-defensin hBD-3 are able to block cell wall biosynthesis by binding to lipid II. Lysozyme is well-characterized to cleave bacterial cell wall polysaccharides but can also kill bacteria by a non-catalytic mechanism. The two hydrophobic domains in the long amphipathic α-helix of human cathelicidin LL-37 lays the basis for binding and disrupting the curved anionic bacterial membrane surfaces by forming pores or via the carpet model. Furthermore, dermcidin may serve as ion channel by forming a long helix-bundle structure. In addition, the C-type lectin RegIIIα can initially recognize bacterial peptidoglycans followed by pore formation in the membrane. Finally, histatin 5 and GAPDH(2-32) can enter microbial cells to exert their effects. It appears that granulysin enters cells and kills intracellular pathogens with the aid of pore-forming perforin. This arsenal of human defense proteins not only keeps us healthy but also inspires the development of a new generation of personalized medicine to combat drug-resistant superbugs, fungi, viruses, parasites, or cancer. Alternatively, multiple factors (e.g., albumin, arginine, butyrate, calcium, cyclic AMP, isoleucine, short-chain fatty acids, UV B light, vitamin D, and zinc) are able to induce the expression of antimicrobial peptides, opening new avenues to the development of anti-infectious drugs.

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Section: Mechanism Of Action Of Human Antimicrobial Peptidesmentioning

confidence: 99%

Human Antimicrobial Peptides and Proteins

2014

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“…They are net-like macromolecules and assembled by the membrane-bound peptidoglycans glycosyltransferases and transpeptidases. The penicillin-type antimicrobials combine to the transpeptidases and inhibit the peptidoglycan formation (Derouaux et al, 2011). Bacterial peptidoglycan transpeptidases are known as penicillin-binding proteins (PBPs) and they are found to be up-regulated in the multidrug-resistant E. coli KD43162 in this study.…”

Section: Sds-page Of Outer Membrane Proteins and Maldi-tof Ms Analysismentioning

confidence: 68%

L-glutamine:D-fructose-6-phosphate Aminotransferase as a Key Protein Linked to Multidrug Resistance in E. coli KD43162

Lee

Jung

Park³

et al. 2015

JABC

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A microarray study has been employed to understand changes of gene expression in E. coli KD43162 resistant to ampicillin, ampicillin-sulbactam, piperacillin, piperacillin-tazobactam, cefazolin, cefepime, aztreonam, imipenem, meropenem, gentamicin, tobramycin, ciprofloxacin, levofloxacin, moxifloxacin, fosfomycin, and trimethoprim-sulfamethoxazole except for amikacin using disk diffusion assay. Using Sodium dodecyl sulphate-polyacrylamide gel electrophoresis and MALDI-TOF MS analyses, 36 kDa of outer membrane proteins (OMPs) was found to be deleted in the multidrug resistant E. coli KD 43162. Microarray analysis was used to determine up-and down-regulated genes in relation to multidrug resistant E. coli KD43162. Among the up-regulated genes, these genes were corresponded to express the proteins as penicillin-binding proteins (PBPs), tartronate semialdehyde reductase, ethanolamine utilization protein, shikimate kinase I, allantoinase, predicted SAM-dependent methyltransferase, Lglutamine:D-fructose-6-phosphate aminotransferase (GFAT), phosphoglucosamine mutase, predicted N-acetylmannosamine kinase, and predicted N-acetylmannosamine-6-P epimerase. Up-regulation of PBPs, one of primary target sites of antibiotics, might be responsible for the multidrug resistance in E. coli with increasing amount of target sites. Up-regulation of GFAT enzyme may be related to the up-regulation of PBPs because GFAT produces N-acetylglucosamine, a precursor of peptidoglycans. One of GFAT inhibitors, azaserine, showed a potent inhibition on the growth of E. coli KD43162. In conclusion, up-regulation of PBPs and GFATs with the loss of 36 kDa OMP refers the multidrug resistance in E. coli KD 43162.

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“…This can allow, therefore, the screening and determination of optimal conditions for multiple transglycosylases from a range of microorganisms, essential in the study of these membrane proteins. In addition, this demonstrated the basis for utility of this assay in library screening of compounds to identify potential novel inhibitors, as did a second study [45].…”

Section: Assays For Transglycosylase Activitymentioning

confidence: 80%