Interception of teicoplanin oxidation intermediates yields new antimicrobial scaffolds

Liu, Yu Chen; Li, Yi-Shan; Lyu, S.Y.; Hsu, Li-Jen; Chen, Yu-Hou; Huang, Yu‐Ting; Chan, H.C.; Huang, Chuen-Jiuan; Chen, Gan-Hong; Chou, Cheng‐Chun; Tsai, Ming‐Daw; Li, Tsung‐Lin

doi:10.1038/nchembio.556

Cited by 60 publications

(43 citation statements)

References 31 publications

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“…The geometry of this disposition is consistent with the hydride ion transfer proposed for many flavin-dependent oxidases 19,20 . This mechanism requires concomitant abstraction of the proton from the C10-OH group, which is likely achieved through the interactions with the invariant Y447 activated by the highly conserved Y136 residue, as proposed for the TamL homolog Dbv29 21 (Fig. 4e, f).…”

Section: Resultsmentioning

confidence: 85%

Tirandamycin biosynthesis is mediated by co-dependent oxidative enzymes

et al. 2011

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Elucidation of natural product biosynthetic pathways provides important insights about the assembly of potent bioactive molecules, and expands access to unique enzymes able to selectively modify complex substrates. Here we show full reconstitution in vitro of an unusual multi-step oxidative cascade for post-assembly line tailoring of tirandamycin antibiotics. This pathway involves a remarkably versatile and iterative cytochrome P450 monooxygenase (TamI) and an FAD-dependent oxidase (TamL), which act co-dependently through repeated exchange of substrates. TamI hydroxylates tirandamycin C (TirC) to generate tirandamycin E (TirE), a heretofore unidentified tirandamycin intermediate. TirE is subsequently oxidized by TamL, giving rise to the ketone of tirandamycin D (TirD), after which a unique exchange back to TamI enables successive epoxidation and hydroxylation to afford, respectively, the final products tirandamycin A (TirA) and tirandamycin B (TirB). Ligand-free, substrate- and product-bound crystal structures of bicovalently flavinylated TamL oxidase reveal a likely mechanism for the C-10 oxidation of TirE.

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Section: Resultsmentioning

confidence: 85%

Tirandamycin biosynthesis is mediated by co-dependent oxidative enzymes

et al. 2011

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“…To initiate these studies, it was necessary to undertake the purification of teicoplanin. 8,22 We targeted teicoplanin A 2 -2 ( 3 , Figure 1) from the readily available mixture of teicoplanins, which is a composite of approximately six to nine molecular forms of teicoplanin (Figure S1). The assignment of the aromatic region of the NMR spectrum of 3 with modern NMR techniques was also essential at the outset of these studies, 22,33-35 as a critical step for analysis and determination of the site of bromination within new products (Figures S1-S3).…”

Section: Introductionmentioning

confidence: 99%

Chemical Tailoring of Teicoplanin with Site-Selective Reactions

Pathak

Miller

2013

J. Am. Chem. Soc.

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Semi-synthesis of natural product derivatives combines the power of fermentation with orthogonal chemical reactions. Yet, chemical modification of complex structures represents an unmet challenge, as poor selectivity often undermines efficiency. The complex antibiotic teicoplanin eradicates bacterial infections. However, as resistance emerges, the demand for improved analogs grows. We have discovered chemical reactions that achieve site-selective alteration of teicoplanin. Utilizing peptide-based additives that alter reaction selectivities, certain bromo-teicoplanins are accessible. These new compounds are also scaffolds for selective cross-coupling reactions, enabling further molecular diversification. These studies enable two-step access to glycopeptide analogs not available through either biosynthesis or rapid total chemical synthesis alone. The new compounds exhibit a spectrum of activities, revealing that selective chemical alteration of teicoplanin may lead to analogs with attenuated or enhanced antibacterial properties, in particular against vancomycin and teicoplanin resistance strains.

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“…Although the structures of several tailoring enzymes have been determined, there is a critical lack of structural information for the enzyme-GPA complexes, which are essential to fully explore and exploit these enzymes. So far, only a few complexes have been structurally identified in which the enzyme is occupied by its glycosylated GPA substrate (5)(6)(7)(8). The value of these structural findings is in the potential for further engineering of GPA-modifying enzymes by structure-guided mutagenesis and other approaches to generate novel antibiotic analogs (7,8).…”

mentioning

confidence: 99%

Sulfonation of glycopeptide antibiotics by sulfotransferase StaL depends on conformational flexibility of aglycone scaffold

Shi

Munger

Kalan

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Although glycopeptide antibiotics (GPAs), including vancomycin and teicoplanin, represent the most important class of antiinfective agents in the treatment of serious Gram-positive bacterial infections, their usefulness is threatened by the emergence of resistant strains. GPAs are complex natural products consisting of a heptapeptide skeleton assembled via nonribosomal peptide synthesis and constrained through multiple crosslinks, with diversity resulting from enzymatic modifications by a variety of tailoring enzymes, which can be used to produce GPA analogues that could overcome antibiotic resistance. GPA-modifying sulfotransferases are promising tools for generating the unique derivatives. Despite significant sequence and structural similarities, these sulfotransferases modify distinct side chains on the GPA scaffold. To provide insight into the spatial diversity of modifications, we have determined the crystal structure of the ternary complex of bacterial sulfotransferase StaL with the cofactor product 3′-phosphoadenosine 5′-phosphate and desulfo-A47934 aglycone substrate. Desulfo-A47934 binds with the hydroxyl group on the 4-hydroxyphenylglycine in residue 1 directed toward the 3′-phosphoadenosine 5′-phosphate and hydrogen-bonded to the catalytic His67. Homodimeric StaL can accommodate GPA substrate in only one of the two active sites because of potential steric clashes. Importantly, the aglycone substrate demonstrates a flattened conformation, in contrast to the cup-shaped structures observed previously. Analysis of the conformations of this scaffold showed that despite the apparent rigidity due to crosslinking between the side chains, the aglycone scaffold displays substantial flexibility, important for enzymatic modifications by the GPA-tailoring enzymes. We also discuss the potential of using the current structural information in generating unique GPA derivatives.substrate binding | substrate flexibility | substrate recognition

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Interception of teicoplanin oxidation intermediates yields new antimicrobial scaffolds

Cited by 60 publications

References 31 publications

Tirandamycin biosynthesis is mediated by co-dependent oxidative enzymes

Tirandamycin biosynthesis is mediated by co-dependent oxidative enzymes

Chemical Tailoring of Teicoplanin with Site-Selective Reactions

Sulfonation of glycopeptide antibiotics by sulfotransferase StaL depends on conformational flexibility of aglycone scaffold

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