Mechanism of action of nucleoside antibacterial natural product antibiotics

Bugg, Timothy D. H.; Kerr, Rachel V.

doi:10.1038/s41429-019-0227-3

Cited by 29 publications

(19 citation statements)

References 91 publications

(92 reference statements)

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“…43,372−375 It also inhibits MraY. 155,158,163,376 Nonetheless, tunicamycin is not suitable as an antibiotic due to eukaryotic toxicity. Its structural modification favorably altered this balance to give tunicamycin analogs showing βlactam synergy, 377 confirming previous observations showing a 16−64-fold MIC decrease for β-lactams for MRSA bacteria in the presence of 0.4 mg L −1 tunicamycin.…”

Section: S Aureus Cell Envelope Beyond the Peptidoglycanmentioning

confidence: 99%

“…Each of these four enzymesUppS, − UppP, − MraY, − and MurG ,− have been explored intensively with respect to inhibition by both synthetic and natural product (antibiotic) molecules. The renewed interest in structure–activity development of the nucleoside-mimetic natural product inhibitors of MraY ,− and the recognition that numerous antibiotics interfere with peptidoglycan biosynthesis by complexation with the undecaprenol diphosphate (in both Gram-positive ,− and Gram-negative bacteria , ) and/or Lipid II ,,,− ) are notable recent developments. Indeed, the recognition of the fastidiousness of the intertwined biosynthetic cycles for Lipid II synthesis, , for Lipid II assembly into the peptidoglycan, and for peptidoglycan recycling (with preeminent natural product antibacterials targeting within each cycle) − have led to substantial effort toward answering whether concurrent inhibition of two of these cycles (and their regulatory systems) achieves meaningful antibiotic synergism.…”

Section: Gram-positive Cell Envelopementioning

confidence: 99%

“…The potential value of Lcp enzyme inhibitionenzymes without a eukaryotic equivalentwith respect to S. aureus chemotherapy is evident. , Equally compelling data emerged across a series of papers examining inhibitors of the enzymes of WTA biosynthesis. Tunicamycin is a natural product inhibitor of TarO, the first enzyme of WTA biosynthesis, and blocks WTA incorporation into the S. aureus cell envelope and causes septal-growth defect. ,− It also inhibits MraY. ,,, Nonetheless, tunicamycin is not suitable as an antibiotic due to eukaryotic toxicity. Its structural modification favorably altered this balance to give tunicamycin analogs showing β-lactam synergy, confirming previous observations showing a 16–64-fold MIC decrease for β-lactams for MRSA bacteria in the presence of 0.4 mg L –1 tunicamycin .…”

Section: Gram-positive Cell Envelopementioning

confidence: 99%

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β-Lactams against the Fortress of the Gram-Positive Staphylococcus aureus Bacterium

Fisher

Mobashery

2020

Chem. Rev.

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The biological diversity of the unicellular bacteriawhether assessed by shape, food, metabolism, or ecological nichesurely rivals (if not exceeds) that of the multicellular eukaryotes. The relationship between bacteria whose ecological niche is the eukaryote, and the eukaryote, is often symbiosis or stasis. Some bacteria, however, seek advantage in this relationship. One of the most successfulto the disadvantage of the eukaryoteis the small (less than 1 μm diameter) and nearly spherical Staphylococcus aureus bacterium. For decades, successful clinical control of its infection has been accomplished using β-lactam antibiotics such as the penicillins and the cephalosporins. Over these same decades S. aureus has perfected resistance mechanisms against these antibiotics, which are then countered by new generations of β-lactam structure. This review addresses the current breadth of biochemical and microbiological efforts to preserve the future of the β-lactam antibiotics through a better understanding of how S. aureus protects the enzyme targets of the β-lactams, the penicillin-binding proteins. The penicillin-binding proteins are essential enzyme catalysts for the biosynthesis of the cell wall, and understanding how this cell wall is integrated into the protective cell envelope of the bacterium may identify new antibacterials and new adjuvants that preserve the efficacy of the β-lactams.

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Section: S Aureus Cell Envelope Beyond the Peptidoglycanmentioning

confidence: 99%

Section: Gram-positive Cell Envelopementioning

confidence: 99%

Section: Gram-positive Cell Envelopementioning

confidence: 99%

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β-Lactams against the Fortress of the Gram-Positive Staphylococcus aureus Bacterium

Fisher

Mobashery

2020

Chem. Rev.

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“…The latter is inserted into the PG layer as a building unit by various penicillin-binding proteins (PBPs) ( Sauvage et al, 2008 ). MraY is a well-studied target for antibiotics and the bacteriophage ϕX174 for host cell lysis in E. coli ( Bernhardt et al, 2000 ; Bugg and Kerr, 2019 ). Because of its rigid nature, PG synthesis and degradation occur constantly during cell growth and division for the morphogenesis of the newly formed cell poles during cell constriction.…”

Section: Introductionmentioning

confidence: 99%

Functions of the Essential Gene mraY in Cellular Morphogenesis and Development of the Filamentous Cyanobacterium Anabaena PCC 7120

et al. 2021

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Bacterial cell shape is determined by the peptidoglycan (PG) layer. The cyanobacterium Anabaena sp. PCC 7120 (Anabaena) is a filamentous strain with ovoid-shaped cells connected together with incomplete cell constriction. When deprived of combined nitrogen in the growth medium, about 5–10% of the cells differentiate into heterocysts, cells devoted to nitrogen fixation. It has been shown that PG synthesis is modulated during heterocyst development and some penicillin-binding proteins (PBPs) participating in PG synthesis are required for heterocyst morphogenesis or functioning. Anabaena has multiple PBPs with functional redundancy. In this study, in order to examine the function of PG synthesis and its relationship with heterocyst development, we created a conditional mutant of mraY, a gene necessary for the synthesis of the PG precursor, lipid I. We show that mraY is required for cell and filament integrity. Furthermore, when mraY expression was being limited, persistent septal PG synthetic activity was observed, resulting in increase in cell width. Under non-permissive conditions, filaments and cells were rapidly lysed, and no sign of heterocyst development within the time window allowed was detected after nitrogen starvation. When mraY expression was being limited, a high percentage of heterocyst doublets were found. These doublets are formed likely as a consequence of delayed cell division and persistent septal PG synthesis. MraY interacts with components of both the elongasome and the divisome, in particular those directly involved in PG synthesis, including HetF, which is required for both cell division and heterocyst formation.

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“…Pacidamycins 1 and 5, cationic peptides with homology to the bacteriophage øX174 lysis protein Arg-Trp-x-x-Trp motif, believed to bind the cytoplasmic surface of MraY and thereby inhibiting it (Figure 1 3 ) (Rodolis et al, 2014; Bugg and Kerr, 2019), had little effect on either growth rate or chloroplast division (data not shown). Likewise, Murgocil, a 448Da steroid-like molecule, which inhibits peptidoglycan synthesis in Staphylococcus aureus and is predicted to bind in the MurG active site blocking UDP-GlcNAc access (Figure 1 5 ), when tested at 1, 5 and 25 µg.ml-1 was found to have little effect on protonemata phenotype (Figure 2, F).…”

mentioning

confidence: 97%

Plant peptidoglycan precursor biosynthesis: Conservation between moss chloroplasts and Gram negative bacteria

Dowson-Day

Lloyd

Cuming

et al. 2022

Preprint

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An accumulation of evidence suggests that peptidoglycan, consistent with a bacterial cell wall, is synthesised around the chloroplasts of many photosynthetic eukaryotes, from glaucophyte algae to land plants at least as evolved as pteridophyte ferns, but the biosynthetic pathway has not been demonstrated. We employed mass spectrometry and enzymology in a two fold approach to characterize the synthesis of peptidoglycan in chloroplasts of the moss Physcomitrium (Physcomitrella) patens. To drive the accumulation of peptidoglycan pathway intermediates, P.patens was cultured with the antibiotics phosphomycin, D-cycloserine and carbenicillin, which inhibit key peptidoglycan pathway proteins in bacteria. Mass spectrometry of the TCA-extracted moss metabolome revealed elevated levels of five of the predicted intermediates from UDP-GlcNAc through to the UDP-MurNAc-D,L-diaminopimelate (DAP)-pentapeptide. Most Gram negative bacteria, including cyanobacteria, incorporate meso-diaminopimelate (D,L-DAP) into the third residue of the stem peptide of peptidoglycan, as opposed to L-Lysine, typical of most Gram positive bacteria. To establish the specificity of D,L-DAP incorporation into the P.patens precursors, we analysed the recombinant protein that appends the third stem peptide amino acid, UDP-MurNAc-tripeptide ligase (MurE), from both P.patens and the cyanobacterium Anabaena sp. strain PCC 7120. Both ligases incorporated D,L-DAP in almost complete preference to L-Lys, consistent with the mass spectrophotometric data, with catalytic efficiencies similar to previously documented Gram negative bacterial MurE ligases. We discuss how these data accord with the conservation of active site residues common to DL-DAP-incorporating bacterial MurE ligases and of the probability of a horizontal gene transfer event within the plant peptidoglycan pathway.

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Mechanism of action of nucleoside antibacterial natural product antibiotics

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Cited by 29 publications

References 91 publications

β-Lactams against the Fortress of the Gram-Positive Staphylococcus aureus Bacterium

β-Lactams against the Fortress of the Gram-Positive Staphylococcus aureus Bacterium

Functions of the Essential Gene mraY in Cellular Morphogenesis and Development of the Filamentous Cyanobacterium Anabaena PCC 7120

Plant peptidoglycan precursor biosynthesis: Conservation between moss chloroplasts and Gram negative bacteria

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