Chemical structure metagenomics of microbial natural products: surveying nonribosomal peptides and beyond

• Thomas Ma and
• John Chu

Beilstein J. Org. Chem. 2024, 20, 3050–3060, doi:10.3762/bjoc.20.253

• the glycopeptide antibiotic family [62][63]. Their aromatic rings undergo oxidative coupling to form biaryl moieties that restrict atropisomerism; the resulting rigid structure is key to their high affinity binding to peptidoglycan intermediates [64][65]. Glycopeptide antibiotics include vancomycin

Optimizations of lipid II synthesis: an essential glycolipid precursor in bacterial cell wall synthesis and a validated antibiotic target

• Milandip Karak,
• Cian R. Cloonan,
• Brad R. Baker,
• Rachel V. K. Cochrane and
• Stephen A. Cochrane

Beilstein J. Org. Chem. 2024, 20, 220–227, doi:10.3762/bjoc.20.22

• analogues through the incorporation of alternative building blocks at different stages of synthesis. Keywords: chemical glycosylation; lipid II; peptidoglycan; polyprenyls; total synthesis; Introduction Lipid II (Figure 1) is an essential bacterial glycolipid involved in peptidoglycan biosynthesis [1]. It

• is synthesized on the inner leaflet of the cytoplasmic membrane, before translocation to the outer leaflet, where it is then used as the monomeric building block of peptidoglycan biosynthesis. Lipid II is a validated antibiotic target for clinically prescribed antibiotics including vancomycin and

Synthesis, docking study and biological evaluation of ᴅ-fructofuranosyl and ᴅ-tagatofuranosyl sulfones as potential inhibitors of the mycobacterial galactan synthesis targeting the galactofuranosyltransferase GlfT2

• Marek Baráth,
• Jana Jakubčinová,
• Zuzana Konyariková,
• Stanislav Kozmon,
• Katarína Mikušová and
• Maroš Bella

Beilstein J. Org. Chem. 2020, 16, 1853–1862, doi:10.3762/bjoc.16.152

• ]. The mycobacterial cell wall core is formed by the mycolyl–arabinogalactan–peptidoglycan (mAGP) complex, which provides a highly hydrophobic and resistant barrier surrounding the bacterium [3]. The galactan component of the cell wall consists of polysaccharide chains composed of approximately 22

Design, synthesis and biological evaluation of immunostimulating mannosylated desmuramyl peptides

• Rosana Ribić,
• Ranko Stojković,
• Lidija Milković,
• Mariastefania Antica,
• Marko Cigler and
• Srđanka Tomić

Beilstein J. Org. Chem. 2019, 15, 1805–1814, doi:10.3762/bjoc.15.174

• University Munich, Lichtenbergstraße 4, D-85748 Garching, Germany Faculty of Science, University of Zagreb, Horvatovac 102a, HR-10000 Zagreb, Croatia 10.3762/bjoc.15.174 Abstract Muramyl dipeptide is the minimal structure of peptidoglycan with adjuvant properties. Replacement of the N-acetylmuramyl moiety

• investigated in the mouse model using ovalbumin as an antigen. Their activities were compared to the previously described mannosylated adamantane-containing desmuramyl peptide and peptidoglycan monomer. Tested compounds exhibited adjuvant activity and the strongest enhancement of IgG production was stimulated

• mammalian hosts and therefore have been extensively studied as possible adjuvants for vaccines. Peptidoglycan is a polymeric component of the Gram-positive and Gram-negative bacterial cell wall. Breakdown products of polymeric peptidoglycan are called muropeptides. Muropeptides act as agonists of pathogen

Lectins of Mycobacterium tuberculosis – rarely studied proteins

• Katharina Kolbe,
• Sri Kumar Veleti,
• Norbert Reiling and
• Thisbe K. Lindhorst

Beilstein J. Org. Chem. 2019, 15, 1–15, doi:10.3762/bjoc.15.1

• membrane is surrounded by a peptidoglycan layer (PG) consisting of multiple, parallel glycan chains of alternating (1→4)-linked subunits of N-acetyl-β-D-glucosamine and N-acetyl- or N-glycolyl-β-D-muramic acid, crosslinked via short conserved oligopeptide stems [44][45]. The PG is covalently attached to

• -D-muramic acid; Neu5Ac: N-acetyl-D-neuraminic acid; PG: peptidoglycan; L-Rhap: L-rhamnopyranosides; sMTL: secreted 13 kDa large lectin from Mtb; TB: tuberculosis; TDM: trehalose 6,6'-dimycolate; TMM: trehalose 6-monomycolate; T4P: type IV pili. Immune cells (e.g., macrophages) and epithelial cells

• main carbohydrates of the Mtb cell envelope, a multi-layered structure composed of a mycolyl–arabinogalactan (AG)–peptidoglycan (PG) complex, the lipoglycans lipomannan (LM), and mannosylated lipoarabinomannan (ManLAM), as well as glycolipids, such as trehalose 6,6'-dimycolate (TDM) and trehalose 6

Biochemical and structural characterisation of the second oxidative crosslinking step during the biosynthesis of the glycopeptide antibiotic A47934

• Veronika Ulrich,
• Clara Brieke and
• Max J. Cryle

Beilstein J. Org. Chem. 2016, 12, 2849–2864, doi:10.3762/bjoc.12.284

• products and are highly effective antibiotics against Gram-positive bacteria, where they affect their function by preventing the correct crosslinking of the peptidoglycan cell wall [1]. Produced by bacteria, these compounds derive their efficacy from their unique three-dimensional structure, which in turn

• enables them to bind to the dipeptide terminus of the peptidoglycan precursor lipid II [1][2]. This three-dimensional structure is generated by the high degree of crosslinking exhibited by the glycopeptide antibiotics: in the case of the two most widely known natural examples (vancomycin and teicoplanin

Enduracididine, a rare amino acid component of peptide antibiotics: Natural products and synthesis

• Darcy J. Atkinson,
• Briar J. Naysmith,
• Daniel P. Furkert and
• Margaret A. Brimble

Beilstein J. Org. Chem. 2016, 12, 2325–2342, doi:10.3762/bjoc.12.226

• transglycosylation during peptidoglycan synthesis [23], the same step inhibited by vancomycin [24]. Enduracidin A (7) and B (8) also exhibited inhibition of avian myeloblastosis virus reverse transcriptase but did not suppress replication of HIV cells [25]. Enduracidin A (7) and B (8) have been produced by

• using traditional techniques. Teixobactin (17) exhibits bactericidal activity through binding of Lipid II, a precursor of peptidoglycan, and therefore shows great potential as the foundation for discovery of a new generation of antibiotics to overcome the development of antimicrobial resistance

• which involves binding to Lipid II, inhibiting one of the membrane-associated steps of peptidoglycan biosynthesis [43][44]. Analogues of teixobactin (17) have undergone biological testing and results show that the L-allo-enduracididine (3, blue, Figure 7) residue is important for potent antibacterial

Cyclisation mechanisms in the biosynthesis of ribosomally synthesised and post-translationally modified peptides

• Andrew W. Truman

Beilstein J. Org. Chem. 2016, 12, 1250–1268, doi:10.3762/bjoc.12.120

• cysteine protease-like mechanism [118]. In vivo, this staphylococcal protein ligates proteins with a C-terminal LPXTG motif to the peptidoglycan, via the formation of an enzyme bound thioester on the threonine residue, and has been used widely as an enzymatic tool for ligation to proteins with an LPXTG tag

Muraymycin nucleoside-peptide antibiotics: uridine-derived natural products as lead structures for the development of novel antibacterial agents

• Daniel Wiegmann,
• Stefan Koppermann,
• Marius Wirth,
• Giuliana Niro,
• Kristin Leyerer and
• Christian Ducho

Beilstein J. Org. Chem. 2016, 12, 769–795, doi:10.3762/bjoc.12.77

• natural products. These uridine-derived nucleoside-peptide antibiotics inhibit the bacterial membrane protein translocase I (MraY), a key enzyme in the intracellular part of peptidoglycan biosynthesis. This review describes the structures of naturally occurring muraymycins, their mode of action, synthetic

• methicillin-resistant Staphylococcus aureus (MRSA) [18][19] and vancomycin-resistant Enterococcus (VRE) [20]. This development raises the demand for antibiotics exploiting yet unused modes of action. Potential targets within bacteria include peptidoglycan biosynthesis, protein biosynthesis, DNA and RNA

• replication and folate metabolism [21]. Promising candidates meeting the requirements for new drugs are nucleoside antibiotics, i.e., uridine-derived compounds that address the enzyme translocase I (MraY) as a novel target, thereby interfering with a membrane-associated intracellular step of peptidoglycan

DNA display of glycoconjugates to emulate oligomeric interactions of glycans

• Alexandre Novoa and
• Nicolas Winssinger

Beilstein J. Org. Chem. 2015, 11, 707–719, doi:10.3762/bjoc.11.81

• solid-phase synthesis have enabled the introduction of complex glycans with modest synthetic investments to obtain the suitably functionalized glycans. Furthermore, methods to access large libraries of peptidoglycan conjugates with nucleic acid tags have been reported opening new horizons in the

Design, automated synthesis and immunological evaluation of NOD2-ligand–antigen conjugates

• Marian M. J. H. P. Willems,
• Gijs G. Zom,
• Nico Meeuwenoord,
• Ferry A. Ossendorp,
• Herman S. Overkleeft,
• Gijsbert A. van der Marel,
• Jeroen D. C. Codée and
• Dmitri V. Filippov

Beilstein J. Org. Chem. 2014, 10, 1445–1453, doi:10.3762/bjoc.10.148

• -binding oligomerization domain (NOD) receptors [17] NOD1 [18] and NOD2 [19] were discovered to be intracellular PRRs [20][21]. NOD1 and NOD2 recognize specific parts of peptidoglycan (PG), found in the bacterial cell wall [22][23]. PG consists of a polysaccharide chain of β-(1–4) linked N

Amino acid motifs in natural products: synthesis of O-acylated derivatives of (2S,3S)-3-hydroxyleucine

• Oliver Ries,
• Martin Büschleb,
• Markus Granitzka,
• Dietmar Stalke and
• Christian Ducho

Beilstein J. Org. Chem. 2014, 10, 1135–1142, doi:10.3762/bjoc.10.113

• derivatives 1a,b of the A- and B-series, respectively (Figure 1) [7]. This significant change in potency might be owed to increased lipophilicity and thus to improved cellular uptake, as muraymycins inhibit the transmembrane protein MraY (translocase I), an enzyme involved in peptidoglycan formation with its

Synthesis and physicochemical characterization of novel phenotypic probes targeting the nuclear factor-kappa B signaling pathway

• Paul M. Hershberger,
• Satyamaheshwar Peddibhotla,
• E. Hampton Sessions,
• Daniela B. Divlianska,
• Ricardo G. Correa,
• Anthony B. Pinkerton,
• John C. Reed and
• Gregory P. Roth

Beilstein J. Org. Chem. 2013, 9, 900–907, doi:10.3762/bjoc.9.103

• bacterial cell-wall components including lipopolysaccharides and/or peptidoglycan (NOD1 or 2) along with those of bacterial flagellin [22][23][24][25]. Importantly, the NOD1 protein primarily recognizes Gram-negative bacteria, in contrast to the more widely studied sensor NOD2, which participates in

Multivalent display of the antimicrobial peptides BP100 and BP143

• Imma Güell,
• Rafael Ferre,
• Kasper K. Sørensen,
• Esther Badosa,
• Iteng Ng-Choi,
• Emilio Montesinos,
• Eduard Bardají,
• Lidia Feliu,
• Knud J. Jensen and
• Marta Planas

Beilstein J. Org. Chem. 2012, 8, 2106–2117, doi:10.3762/bjoc.8.237

• demonstrated that the large volume and the charge of the bundles made their passage through the peptidoglycan or the lipopolysaccharide layers difficult, therefore preventing them from accessing the inner membrane. In contrast, despite the fact that a significant decrease of the MIC values was not observed

Design of a novel tryptophan-rich membrane-active antimicrobial peptide from the membrane-proximal region of the HIV glycoprotein, gp41

• Evan F. Haney,
• Leonard T. Nguyen,
• David J. Schibli and
• Hans J. Vogel

Beilstein J. Org. Chem. 2012, 8, 1172–1184, doi:10.3762/bjoc.8.130

• attempts to resolve the NMR structure of gp41w in aqueous solution or 40% TFE were unsuccessful because of peptide aggregation or poor solubility [12]. In terms of the antimicrobial activity, gp41w oligomers may be too large to pass through the peptidoglycan layer surrounding Gram-positive bacteria

Facile synthesis of nitrophenyl 2-acetamido-2-deoxy-α-D-mannopyranosides from ManNAc-oxazoline

• Karel Křenek,
• Petr Šimon,
• Lenka Weignerová,
• Barbora Fliedrová,
• Marek Kuzma and
• Vladimír Křen

Beilstein J. Org. Chem. 2012, 8, 428–432, doi:10.3762/bjoc.8.48

• yielding a separable mixture of the o- and p-nitrophenyl derivative in a 2:3 ratio. Keywords: α-ManNAc; glycosidase; glycosylation; nitrophenyl; oxazoline; Introduction Hexosamines are fundamental structural elements and precursors of the peptidoglycan and membrane lipopolysaccharide layer as well as of

Synthesis of glycoconjugate fragments of mycobacterial phosphatidylinositol mannosides and lipomannan

• Benjamin Cao,
• Jonathan M. White and
• Spencer J. Williams

Beilstein J. Org. Chem. 2011, 7, 369–377, doi:10.3762/bjoc.7.47

• major component being a macromolecule composed of mycolic acids, arabinogalactan, and peptidoglycan, termed the mycolyl–arabinogalactan–peptidoglycan complex [6][7]. One intriguing class of cell wall associated molecules are those based on a phosphatidylinositol (PI) core, which include the PIMs, LM