A review on cell wall synthesis inhibitors with an emphasis on glycopeptide antibiotics

Sarkar, Paramita; Yarlagadda, Venkateswarlu; Ghosh, Chandradhish; Haldar, Jayanta

doi:10.1039/c6md00585c

Cited by 144 publications

(121 citation statements)

References 130 publications

(172 reference statements)

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“…Table S1). These antibiotics included fosfomycin (FOS; 2.5 mg/ml), which inhibits MurA, the catalyst in the first step of cell wall synthesis; tunicamycin (TUN; 2.5 μg/ml), which inhibits MraY and TagO, which are respectively involved in lipid II and wall teichoic acid (WTA) synthesis 86,87 ; and ampicillin (AMP; 1 mg/ml) and vancomycin (VAN; 5 μg/ml), which inhibit the last incorporation step of cell wall precursor into the existing cell wall 88 . The lateral mobility of the FloA and FloT assemblies was monitored during the inhibition of cell wall synthesis using time-lapse fluorescence microscopy every 300 ms over 9 s. Treatment with any of these antibiotics at concentrations that inhibited cell wall synthesis reduced the diffusion coefficients of FloA and FloT (Fig.…”

Section: Resultsmentioning

confidence: 99%

The Bacterial Cytoskeleton Spatially Confines Functional Membrane Microdomains

Machta

et al. 2020

Preprint

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22Cell membranes laterally segregate into microdomains enriched in certain lipids and scaffold 23 proteins. Membrane microdomains modulate protein-protein interactions and are essential for cell 24 polarity, signaling and membrane trafficking. How cells organize their membrane microdomains, and 25 the physiological importance of these microdomains, is unknown. In eukaryotes, the cortical actin 26 cytoskeleton is proposed to act like a fence, constraining the dynamics of membrane microdomains. 27Like their eukaryotic counterparts, bacterial cells have functional membrane microdomains (FMMs) 28 that act as platforms for the efficient oligomerization of protein complexes. In this work, we used the 29 model organism Bacillus subtilis to demonstrate that FMM organization and movement depend 30 primarily on the interaction of FMM scaffold proteins with the domains' protein cargo, rather than with 31 domain lipids. Additionally, the MreB actin-like cytoskeletal network that underlies the bacterial 32 membrane was found to frame areas of the membrane in which FMM mobility is concentrated. 33Variations in membrane fluidity did not affect FMM mobility whereas alterations in cell wall organization 34 affected FMM mobility substantially. Interference with MreB organization alleviates FMM spatial 35 confinement whereas, by contrast, inhibition of cell wall synthesis strengthens FMM confinement. The 36 restriction of FMM lateral mobility by the submembranous actin-like cytoskeleton or the extracellular 37 wall cytoskeleton appears to be a conserved mechanism in prokaryotic and eukaryotic cells for 38 localizing functional protein complexes in specific membrane regions, thus contributing to the 39 organization of cellular processes. 40 41 42 43 48 actually heterogeneous fluids, with different membrane lipid species laterally segregating into sub-49 micrometer domains, driven by their physico-chemical properties 2-4 . This heterogeneous organization 50 of membrane lipids leads to a heterogeneous distribution of the embedded membrane proteins, which 51 appears essential for their functionality 5 . Membrane microdomains are widely present, mobile 52 structures that vary in size from transient protein clusters measured in nm 6 to large micron-sized stable 53 domains such as desmosomes 7 . These domains harbor proteins specialized in membrane trafficking, 54 cell-cell adhesion, and signal transduction, and they provide targets for viral entry 8 . 56It is now appreciated that membrane proteins can significantly impact membrane organization, in 57 particular stabilizing membrane domains. For instance, the scaffold activity of the flotillin proteins FLO1 58 and FLO2 plays an important role in stabilizing some eukaryotic membrane rafts ("lipid rafts") 9-11 ; it 59 would seem that this raft organization occurs in part through the capture and stabilization of specific 60 lipids by flotillins 12,13 . In addition, the activity of the flotillin scaffold contributes to the recruitment of 61 other raft-associated proteins, thus facilitatin...

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Section: Resultsmentioning

confidence: 99%

The Bacterial Cytoskeleton Spatially Confines Functional Membrane Microdomains

Machta

et al. 2020

Preprint

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“…Similarly, MC02 T also does not possess an α-galactosidase gene to hydrolyse melibiose [54]. In contrast to some of the other Massilia strains, MC02 T showed resistance against the two antibiotics vancomycin and rifamycin SV, which inhibit bacterial cell wall biosynthesis and the DNA-dependent RNA polymerase, respectively [55,56].…”

Section: Physiological and Metabolic Characteristicsmentioning

confidence: 99%

Massilia arenosa sp. nov., isolated from the soil of a cultivated maize field

Raths

Peta

Bücking

2020

International Journal of Systematic and Evolutionary Microbiology

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Strain MC02T, a Gram-stain-negative, rod-shaped bacterium, was isolated from field soil collected from California, USA. To examine if MC02T represents a novel species, we compared its colony morphology, 16S rRNA gene and whole genome sequence, and its metabolic phenotype using Biolog GenIII and MALDI-TOF analyses compared to reference strains. Based on 16S rRNA gene and whole genome sequencing, MC02T belongs to the genus Massilia and Massilia agri K-3–1T is the most similar strain with 96.97 % 16S rRNA gene sequence identity. MALDI-TOF analysis revealed that Massilia aerilata DSM19289T is the closest match, but the similarity score was much lower than the ≥1.7 threshold for a reliable identification at the genus level. The predominant fatty acids were summed feature 3 (C16 : 1⍵7c and/or C16 : 1⍵6c; 49.07 %) and C16 : 0 (30.01 %). The genome is 5.02 Mbp and the G+C content is 66.2 mol%. Whole genome comparisons to the closest related strains revealed an average amino acid identity value of 67.4 %, an OrthoANI similarity of 77.1 %, and a DNA–DNA-hybridization probability ≥70 %, confirming that MC02T represents a novel species. Strain MC02T can grow at pH 6 but not at pH 5, and a salt concentration of ≥1 % inhibits its growth. In contrast to other Massilia strains, MC02T can utilize turanose, inosine and l-serine. The genome of MC02T shows putative endophyte genes such as a nitrate reductase, several phosphatases, and biotin biosynthesis genes, 26 flagellar motility genes and 14 invasion and intracellular resistance genes. Based on its metabolic, physiological and genomic characteristics, we propose that strain MC02T (NRRL B-65554T=ATCC TSD-200T=LMG 31737T) represents a novel species of the genus Massilia with the name Massilia arenosa sp. nov.

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“…Ideally, candidate drugs should target unexploited, vulnerable essential proteins in order to be incorporated into first‐ and second‐line treatments. Several classes of antibiotics inhibit steps in cell‐wall biosynthesis, and therefore, novel enzyme targets crucial to these processes make for good drug targets …”

Section: Introductionmentioning

confidence: 99%

“…Several classes of antibiotics inhibit steps in cell-wall biosynthesis, and therefore, novel enzyme targets crucial to these processes make for good drug targets. 2 Two such enzymes that play integral roles in Mtb's cell wall biosynthesis are the PPTases AcpS and PptT. 3 PPTases catalyze the attachment of the phosphopantetheine arm of coenzyme A (CoA) onto client carrier proteins associated with synthases and synthetases, activating them from inactive apo to active holo form.…”

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confidence: 99%

Structural insights into phosphopantetheinyl hydrolase PptH from Mycobacterium tuberculosis

et al. 2020

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The amidinourea 8918 was recently reported to inhibit the type II phosphopantetheinyl transferase (PPTase) of Mycobacterium tuberculosis (Mtb), PptT, a potential drug‐target that activates synthases and synthetases involved in cell wall biosynthesis and secondary metabolism. Surprisingly, high‐level resistance to 8918 occurred in Mtb harboring mutations within the gene adjacent to pptT, rv2795c, highlighting the role of the encoded protein as a potentiator of the bactericidal action of the amidinourea. Those studies revealed that Rv2795c (PptH) is a phosphopantetheinyl (PpT) hydrolase, possessing activity antagonistic with respect to PptT. We have solved the crystal structure of Mtb's phosphopantetheinyl hydrolase, making it the first phosphopantetheinyl (carrier protein) hydrolase structurally characterized. The 2.5 Å structure revealed the hydrolases' four‐layer (α/β/β/α) sandwich fold featuring a Mn‐Fe binuclear center within the active site. A structural similarity search confirmed that PptH most closely resembles previously characterized metallophosphoesterases (MPEs), particularly within the vicinity of the active site, suggesting that it may utilize a similar catalytic mechanism. In addition, analysis of the structure has allowed for the rationalization of the previously reported PptH mutations associated with 8918‐resistance. Notably, differences in the sequences and predicted structural characteristics of the PpT hydrolases PptH of Mtb and E. coli's acyl carrier protein hydrolase (AcpH) indicate that the two enzymes evolved convergently and therefore are representative of two distinct PpT hydrolase families.

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A review on cell wall synthesis inhibitors with an emphasis on glycopeptide antibiotics

Cited by 144 publications

References 130 publications

The Bacterial Cytoskeleton Spatially Confines Functional Membrane Microdomains

The Bacterial Cytoskeleton Spatially Confines Functional Membrane Microdomains

Massilia arenosa sp. nov., isolated from the soil of a cultivated maize field

Structural insights into phosphopantetheinyl hydrolase PptH from Mycobacterium tuberculosis

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