Crystal Structure and Total Synthesis of Globomycin:  Establishment of Relative and Absolute Configurations

Kogen, Hiroshi; Kiho, Toshihiro; Nakayama, Mizuka; Furukawa, Y.; Kinoshita, and Takeshi; Inukai, Masatoshi

doi:10.1021/ja002547j

Cited by 42 publications

(21 citation statements)

References 12 publications

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“…Mass spectra were acquired in centroid mode ranging from 200 to 2000 m/z (amaZon) or from 150 to 2500 m/z (maXis 4 G) in positive ionization mode with auto MS-MS fragmentations. NMR spectra (1 H, 2D) were recorded on a Bruker Ascend 700 spectrometer with a 5 mm TXI cryoprobe (1 H at 700 MHz, 13 C at 175 MHz) at ambient temperature using standard pulse programs and results compared to the literature 38 . Final purity was estimated at >95% by LCMS, HRMS and NMR.…”

Section: Methodsmentioning

confidence: 99%

Structures of lipoprotein signal peptidase II from Staphylococcus aureus complexed with antibiotics globomycin and myxovirescin

Olatunji

Bailey

et al. 2020

Nat Commun

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Antimicrobial resistance is a major global threat that calls for new antibiotics. Globomycin and myxovirescin are two natural antibiotics that target the lipoprotein-processing enzyme, LspA, thereby compromising the integrity of the bacterial cell envelope. As part of a project aimed at understanding their mechanism of action and for drug development, we provide high-resolution crystal structures of the enzyme from the human pathogen methicillinresistant Staphylococcus aureus (MRSA) complexed with globomycin and with myxovirescin. Our results reveal an instance of convergent evolution. The two antibiotics possess different molecular structures. Yet, they appear to inhibit identically as non-cleavable tetrahedral intermediate analogs. Remarkably, the two antibiotics superpose along nineteen contiguous atoms that interact similarly with LspA. This 19-atom motif recapitulates a part of the substrate lipoprotein in its proposed binding mode. Incorporating this motif into a scaffold with suitable pharmacokinetic properties should enable the development of effective antibiotics with built-in resistance hardiness.

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Section: Methodsmentioning

confidence: 99%

Structures of lipoprotein signal peptidase II from Staphylococcus aureus complexed with antibiotics globomycin and myxovirescin

Olatunji

Bailey

et al. 2020

Nat Commun

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“…Tertiary amides reveal much greater tendency to adopt the cis configuration because introduction of the alkyl group in the place of the amide hydrogen atom increases the steric crowding around the amide moiety and lower rotational barrier around C–N amide bond 52. It is commonly known that N ‐methylation promotes the trans – cis isomerization of the amide bond 53–62. Among standard amino acid, only proline has secondary amine group, and thus, the N ‐terminal proline tertiary amide bond occur to some extend in the cis configuration in proteins 39.…”

Section: Resultsmentioning

confidence: 99%

The cis‐trans isomerization of N‐methyl‐α,β‐dehydroamino acids

et al. 2012

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Dehydroamino acids with the methylated N-terminal peptide group occur in natural small cyclic peptides. The structural analysis was used to investigate the cis-trans isomerization of the N-terminal tertiary amide group of diamides: Ac-(Z)-Δ(Me)Abu-NHMe (1), Ac-(Z)-Δ(Me)Phe-NHMe (2), Ac-(E)-Δ(Me)Phe-NHMe (3), Ac-Δ(Me)Ala-NHMe (4), and Ac-(Me)Ala-NHMe (5). The compounds were analyzed in the solid state by an X-ray crystallography (1-3), and in the solution by FTIR (MeCN and CHCl(3) ) and NMR (DMSO-d6 and CDCl(3) ) methods (1-5). In the solid state, the studied compounds adopt the cis configuration of N-terminal amide. In solution, this configuration also prevails for the dehydroamino acids 1-4, in contrast to the saturated analog 5. The results indicate that N-methyldehydroamino acids present a promising tool to induce the cis configuration of the amide bond.

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“…The LD 50 value for intraperitoneal injection in mice was 115 mg/kg, but mice tolerated up to 400 mg/kg when administered subcutaneously. 57 The total solution synthesis and structure-activity relationship (SAR) study reported by Kogen et al 58,65 showed that the hydroxyl group in the Ser 3 residue is essential for antibacterial activity, and the presence of a longer fatty acid side chain significantly increased the activity. A four-carbon atom increase in the fatty acid side chain length, from nine to thirteen carbons, led to a four-to eight-fold increase in activity against all Gramnegative bacteria tested.…”

Section: Li-f/fusaricidinsmentioning

confidence: 99%

Cyclic Lipodepsipeptides in Novel Antimicrobial Drug Discovery

Bionda¹,

Čudić²

2011

Croat. Chem. Acta

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Abstract. Naturally occurring cyclic depsipeptides, microbial secondary metabolites that contain one or more ester bonds in addition to the amide bonds, have emerged as an important source of pharmacologically active compounds or promising lead structures for the development of novel synthetically derived drugs. In particular, their lipidated derivatives have shown the greatest therapeutic potential as antimicrobial agents. Some of those compounds are either already marketed (daptomycin 37) or in advanced stages of clinical development (ramoplanin 32) for the treatment of complicated infections caused by multidrug-resistant bacterial strains. As bacteria progressively become resistant to frontline antimicrobial agents, our capacity to effectively treat bacterial infections becomes severely hindered. Therefore, identifying novel antibacterial targets and new antibacterial chemotherapeutics capable of treating infections from drug-resistant microorganisms is of vital importance.(doi: 10.5562/cca1819)

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Crystal Structure and Total Synthesis of Globomycin: Establishment of Relative and Absolute Configurations

Cited by 42 publications

References 12 publications

Structures of lipoprotein signal peptidase II from Staphylococcus aureus complexed with antibiotics globomycin and myxovirescin

Structures of lipoprotein signal peptidase II from Staphylococcus aureus complexed with antibiotics globomycin and myxovirescin

The cis‐trans isomerization of N‐methyl‐α,β‐dehydroamino acids

Cyclic Lipodepsipeptides in Novel Antimicrobial Drug Discovery

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