A crystal structure of a dimer of the antibiotic ramoplanin illustrates membrane positioning and a potential Lipid II docking interface

Hamburger, James B.; Hoertz, Amanda J.; Lee, Amy; Senturia, Rachel; McCafferty, Dewey G.; Loll, Patrick J.

doi:10.1073/pnas.0904686106

Cited by 42 publications

(50 citation statements)

References 48 publications

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“…In 2009 McCafferty and colleagues reported the first x-ray structure of ramoplanin A2, demonstrating that the compound exists in the crystal as an amphiphatic dimer with C 2 -symmetry. The mutual orientation of monomers permits the interaction of amino acid residues 9–15 and the formation of six intermolecular hydrogen bonds, resulting in a four-stranded antiparallel β-sheet [101]. The remarkable ability of compound 7 to form dimers in a hydrophobic solvent that mimics the environment at the bacterial cell surface and in the crystal, strongly supports previous findings about the way this antibiotic interacts with its bacterial target, Lipid II ( vide infra ).…”

Section: Ramoplanins/enduracidinssupporting

confidence: 73%

Cyclic Lipodepsipeptides: A New Class of Antibacterial Agents in the Battle Against Resistant Bacteria

2013

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In order to provide effective treatment options for infections caused by multidrug-resistant bacteria, innovative antibiotics are necessary, preferably with novel modes of action and/or belonging to novel classes of drugs. Naturally occurring cyclic lipodepsipeptides, which contain one or more ester bonds along with the amide bonds, have emerged as promising candidates for the development of new antibiotics. Some of these natural products are either already marketed or in advanced stages of clinical development. However, despite the progress in the development of new antibacterial agents, it is inevitable that resistant strains of bacteria will emerge in response to the widespread use of a particular antibiotic and limit its lifetime. Therefore, development of new antibiotics remains our most efficient way to counteract bacterial resistance.

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Section: Ramoplanins/enduracidinssupporting

confidence: 73%

Cyclic Lipodepsipeptides: A New Class of Antibacterial Agents in the Battle Against Resistant Bacteria

2013

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“…We also showed that the lipid side chain is essential for antimicrobial activity (200–800-fold reduction) and, in collaboration with Walker, showed it has no impact on lipid II binding or transglycosylase inhibition, indicating that its role is likely to anchor the antibiotic to the bacterial cell wall. 54 Complementing these studies on the stable amide-modified ramoplanin 9 and other related studies, 61 Suzanne Walker used inhibition kinetics and binding assays to establish that ramoplanin preferentially inhibits the transglycosylase versus MurG catalyzed reactions of their substrates lipid II versus lipid I, that it exhibits a greater affinity for lipid II ( K D = 3 nM) than lipid I ( K D = 170 nM), and that it binds with a 2:1 stoichiometry consistent with functional dimerization. 49,50 …”

Section: Introductionmentioning

confidence: 99%

The Difference a Single Atom Can Make: Synthesis and Design at the Chemistry–Biology Interface

Boger

2017

J. Org. Chem.

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A Perspective of work in our laboratory on the examination of biologically active compounds, especially natural products, is presented. In the context of individual programs and along with a summary of our work, selected cases are presented that illustrate the impact single atom changes can have on the biological properties of the compounds. The examples were chosen to highlight single heavy atom changes that improve activity, rather than those that involve informative alterations that reduce or abolish activity. The examples were also chosen to illustrate that the impact of such single-atom changes can originate from steric, electronic, conformational, or H-bonding effects, from changes in functional reactivity, from fundamental intermolecular interactions with a biological target, from introduction of a new or altered functionalization site, or from features as simple as improvements in stability or physical properties. Nearly all the examples highlighted represent not only unusual instances of productive deep-seated natural product modifications and were introduced through total synthesis but are also remarkable in that they are derived from only a single heavy atom change in the structure.

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“…planin sequesters lipid II at the interface between the extracellular environment and the bacterial membrane and binds the reducing end of the nascent glycan chain (9,12,13). The lantibiotic nisin recognizes the diphospho-sugar portion of lipid II (17).…”

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confidence: 99%

The Bacillus subtilis GntR Family Repressor YtrA Responds to Cell Wall Antibiotics

et al. 2011

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The transglycosylation step of cell wall synthesis is a prime antibiotic target because it is essential and specific to bacteria. Two antibiotics, ramoplanin and moenomycin, target this step by binding to the substrate lipid II and the transglycosylase enzyme, respectively. Here, we compare the ramoplanin and moenomycin stimulons in the Gram-positive model organism Bacillus subtilis. Ramoplanin strongly induces the LiaRS two-component regulatory system, while moenomycin almost exclusively induces genes that are part of the regulon of the extracytoplasmic function (ECF) factor M . Ramoplanin additionally induces the ytrABCDEF and ywoBCD operons, which are not part of a previously characterized antibiotic-responsive regulon. Cluster analysis reveals that these two operons are selectively induced by a subset of cell wall antibiotics that inhibit lipid II function or recycling. Repression of both operons requires YtrA, which recognizes an inverted repeat in front of its own operon and in front of ywoB. These results suggest that YtrA is an additional regulator of cell envelope stress responses.The bacterial cell wall is a unique and vital molecular sieve. It provides the cell with structural strength and protects it from lysis due to high turgor pressures. This makes the cell wall an important target for many antimicrobial compounds (43). The major component of the cell wall is peptidoglycan (PG), an alternating polymer of the amino sugars N-acetylglucosamine (GlcNAc) and N-acetylmuramic acid (MurNAc). GlcNAc and MurNAc are synthesized inside the cell and incorporated, together with a pentapeptide side chain, into the lipid-linked PG precursor designated lipid II. After lipid II is translocated to the outside cell, the GlcNAc-MurNAc-pentapepide portion is inserted and cross-linked to the existing PG by the transglycosylase (TG) and transpeptidase (TP) activities of high-molecular-weight penicillin binding proteins (HMW PBPs).The TG and TP reactions are both excellent drug targets, because they are essential, are easily accessible, and have no equivalent in eukaryotic cells. The TP reaction is specifically targeted by ␤-lactam antibiotics, which covalently modify the enzyme active site. The TG reaction is inhibited by several classes of antibiotics targeting either the substrate or the enzyme. Moenomycin (MOE) is a glycolipid that targets the active site of the TG enzyme (23). Among the TG inhibitors that bind lipid II, the glycopeptides vancomycin, teicoplanin, and ristocetin bind to the terminal D-Ala-D-Ala of the pentapeptide side chain (21, 30). The glycolipodepsipeptide ramoplanin sequesters lipid II at the interface between the extracellular environment and the bacterial membrane and binds the reducing end of the nascent glycan chain (9, 12, 13). The lantibiotic nisin recognizes the diphospho-sugar portion of lipid II (17). Bacitracin, a cyclic dodecylpeptide antibiotic, binds to the undecaprenyl pyrophosphate released after the TG reaction and thereby inhibits the recycling of the key undecaprenyl phosphate li...

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A crystal structure of a dimer of the antibiotic ramoplanin illustrates membrane positioning and a potential Lipid II docking interface

Cited by 42 publications

References 48 publications

Cyclic Lipodepsipeptides: A New Class of Antibacterial Agents in the Battle Against Resistant Bacteria

Cyclic Lipodepsipeptides: A New Class of Antibacterial Agents in the Battle Against Resistant Bacteria

The Difference a Single Atom Can Make: Synthesis and Design at the Chemistry–Biology Interface

The Bacillus subtilis GntR Family Repressor YtrA Responds to Cell Wall Antibiotics

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