Total Syntheses of Bulgecins A, B, and C and Their Bactericidal Potentiation of the β-Lactam Antibiotics

Tomoshige, Shusuke; Dik, David A.; Akabane‐Nakata, Masaaki; Madukoma, Chinedu S.; Fisher, Jed F.; Shrout, Joshua D.; Mobashery, Shahriar

doi:10.1021/acsinfecdis.8b00105

Cited by 26 publications

(31 citation statements)

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“…Moreover, the operon for bulgecin biosynthesis in the bacterium Paraburkholderia acidophilia is contiguous with that of the monobactam‐class β‐lactam, sulfazecin . The presumption that P. acidophilia coordinates the biosynthetic production of the bulgecins with sulfazecin was implicitly validated by the studies of Imada et al and our own recent findings . More recently we documented selectivity in inhibition of the members of the LT family .…”

Section: Abetting the β‐Lactam Antibiotics Against Gram‐negative Bactsupporting

confidence: 51%

“…[297][298][299] The presumption that P. acidophilia coordinates the biosynthetic production of the bulgecins with sulfazecin was implicitly validated by the studies of Imada et al 300 and our own recent findings. 301 More recently we documented selectivity in inhibition of the members of the LT family. 294,302 The target for bulgecins would appear to be the Slt, MltD, and MltG LTs out of the 11 known P. aeruginosa LTs.…”

Section: Abetting the β-Lactam Antibiotics Against Gram-negative Bamentioning

confidence: 99%

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Constructing and deconstructing the bacterial cell wall

Fisher

Mobashery

2019

Protein Science

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The history of modern medicine cannot be written apart from the history of the antibiotics. Antibiotics are cytotoxic secondary metabolites that are isolated from Nature. The antibacterial antibiotics disproportionately target bacterial protein structure that is distinct from eukaryotic protein structure, notably within the ribosome and within the pathways for bacterial cell‐wall biosynthesis (for which there is not a eukaryotic counterpart). This review focuses on a pre‐eminent class of antibiotics—the β‐lactams, exemplified by the penicillins and cephalosporins—from the perspective of the evolving mechanisms for bacterial resistance. The mechanism of action of the β‐lactams is bacterial cell‐wall destruction. In the monoderm (single membrane, Gram‐positive staining) pathogen Staphylococcus aureus the dominant resistance mechanism is expression of a β‐lactam‐unreactive transpeptidase enzyme that functions in cell‐wall construction. In the diderm (dual membrane, Gram‐negative staining) pathogen Pseudomonas aeruginosa a dominant resistance mechanism (among several) is expression of a hydrolytic enzyme that destroys the critical β‐lactam ring of the antibiotic. The key sensing mechanism used by P. aeruginosa is monitoring the molecular difference between cell‐wall construction and cell‐wall deconstruction. In both bacteria, the resistance pathways are manifested only when the bacteria detect the presence of β‐lactams. This review summarizes how the β‐lactams are sensed and how the resistance mechanisms are manifested, with the expectation that preventing these processes will be critical to future chemotherapeutic control of multidrug resistant bacteria.

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Section: Abetting the β‐Lactam Antibiotics Against Gram‐negative Bactsupporting

confidence: 51%

Section: Abetting the β-Lactam Antibiotics Against Gram-negative Bamentioning

confidence: 99%

Constructing and deconstructing the bacterial cell wall

Fisher

Mobashery

2019

Protein Science

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“…Over the next decade, more advanced generation cephalosporins, as well as β-lactam-β-lactamase inhibitor combinations, carbapenems and fluoroquinolones were introduced into the clinic to address the growing problem of Gram negative resistance. Recently a natural product synthesis of the bulgecins was reported for the first time by Tomoshige et al [36] prompting renewed interest in the use of Bulgecin A as an antimicrobial adjuvant, and possible drug optimization via medicinal chemistry.…”

Section: Bulgecins As Lt Inhibitorsmentioning

confidence: 99%

“…The Bulgecin A-meropenem combinations proved effective whether carbapenem resistance was due to the presence of MBLs (VIM-1), hyperproduction of PDC (Amp C enzyme of P. aeruginosa in combination with OMP loss) or efflux. Tomoshige et al using synthetic Bulgecin A were able to demonstrate bulge formation in P. aeruginosa PA01 as well as lysis in the presence of ceftazidime [36].…”

Section: Microbiological Effects Of Bulgecin Amentioning

confidence: 99%

Bulgecins as β-Lactam Enhancers Against Multidrug Resistant (MDR) Pseudomonas aeruginosa

Skalweit¹

2019

Pseudomonas Aeruginosa - An Armory Within

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Antibiotic resistance in non-lactose fermenting pathogens such as Pseudomonas aeruginosa (P. aeruginosa) is increasing, making these clinical pathogens more difficult to treat. Multiple resistance mechanisms exist within P. aeruginosa that affect all classes of antibiotics used in the clinic. New strategies and treatment targets within these MDR pathogens must be exploited. One heretofore untapped target is the family of cell wall enzymes known as lytic transglycosylases (Lts). Lts work in concert with penicillin binding proteins (PBPs) and other cell wall proteins such as amidases and peptidoglycan hydrolases to affect normal cell division, and during stress and programmed cell death. Lts are inhibited by natural products called bulgecins, produced by non-pathogenic Paraburkholderia and Burkholderia spp. New research describing the ability of Lt inhibition to restore susceptibility to β-lactams in MDR P. aeruginosa, as well as the structural biologic basis for the activity of bulgecins will be reviewed. Other targets and applications of bulgecins will also be discussed.

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“…The activities of LTs are known to be inhibited by β-hexosaminidase inhibitors (for example, NAG-thiazoline); bulgecins A, B and C; and PG- O -acetylation 4,10,15,16 . PG- O -acetylation 17 is a process that allows pathogenic bacteria to subvert the host innate immune response 18,19 .…”

Section: Introductionmentioning

confidence: 99%

Crippling the bacterial cell wall molecular machinery

Williams

Wheeler

Deghmane

et al. 2019

Preprint

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34Lytic transglycosylases (LT) are redundant enzymes that play a critical role in 35 peptidoglycan (PG) recycling and metabolism. LT(s) role in cell wall-modifying 36 complexes and usefulness as antimicrobial drug targets remain elusive. We determined at 37 high-resolution a structure of the membrane-bound homolog of the soluble LT from 38 Neisseria species with a disordered active site helix (alpha helix 30). Alpha helix 30 is 39 crucial for binding PG during catalysis 1 . Here we show using an alpha helix 30 deletion 40 strain that LT (LtgA) determines the integrity of the cell wall, participates in cell division 41 and separation, and can be manipulated to impair the fitness of the human pathogen 42 Neisseria meningitidis during infection. Characterization of ltgA helix deleted strain 43 interactome identified glycan chain remodeling enzymes whose function appear to be 44 modulated by LTs. Targeting LTs can disrupt the PG machinery, which is fatal for the 45 bacterium, a new approach for antibiotic development. 46 47 65 alpha helices (α 28, 29, 30, 31, 32, 33, 34, 35, 36, 37), with a six-alpha-helix bundle (α 66 29, 30, 31, 32, 33, 34) constituting the core of the active site that firmly secures the 67 glycan chain ( Fig. 1a). 68 LTs utilize a single catalytic residue, either a glutamate or aspartate, which plays 69 the role of an acid and then that of a base 7-11 . In our recent study, active LtgA was 70 monitored for the first time in the crystalline state, and the residues involved in the 71 substrate and product formation steps were identified. Globally, conformational changes 72 occurred in three domains, the U, C and L domains, between native LtgA and LtgA 73 bound to the product 5 . Substantial conformational changes were observed in the active 74 site, for example, during the product formation step, the active site adopted a more open 75 conformation 5 . 76 Many Gram-negative bacteria have multiple and redundant LTs; for example, 77 Escherichia coli has eight (MltA, MltB, MltC, MltD, MltE, MltF, MltG and Slt70), and 78 4 Neisseria species encodes 5 (LtgA, LtgB, LtgC, LtgD, and LtgE), suggesting that LT 79 activity is vital to the life cycle of the cell 12 . Because the activity of LTs is redundant, the 80 loss of one or more LTs in E. coli leads to no observable growth defects. When genes for 81 6 LTs were deleted from E. coli, a mild chaining phenotype was observed 13 . However, 82 despite lack of strong observable phenotypic changes, it has been suggested that LTs may 83 have well-defined roles in the cell. For example, the deletion of ltgA and ltgD in 84 Neisseria gonorrhoeae eliminates the release of cytotoxic PG monomers suggesting the 85 activity of LtgA and LtgD are redundant. Moreover, LtgA primarily localizes at the 86 septum, indicating a role in the divisome machinery; whereas, LtgD is distributed along 87 the entire cell surface 14 . 88 The activities of LTs are known to be inhibited by β-hexosaminidase inhibitors 89 (for example, NAG-thiazoline); bulgecins A, B and C;...

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Total Syntheses of Bulgecins A, B, and C and Their Bactericidal Potentiation of the β-Lactam Antibiotics

Cited by 26 publications

References 58 publications

Constructing and deconstructing the bacterial cell wall

Constructing and deconstructing the bacterial cell wall

Bulgecins as β-Lactam Enhancers Against Multidrug Resistant (MDR) Pseudomonas aeruginosa

Crippling the bacterial cell wall molecular machinery

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