Ramoplanin

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Dale L. Boger - One of the best experts on this subject based on the ideXlab platform.

  • Vancomycin, Teicoplanin, and Ramoplanin: Synthetic and Mechanistic Studies
    ChemInform, 2010
    Co-Authors: Dale L. Boger
    Abstract:

    Vancomycin, teicoplanin, and Ramoplanin are potent glycopeptide antibiotics that act by inhibiting bacterial cell wall biosynthesis. The former are used clinically as the antibiotics of last resort for the treatment of methicillin-resistant Staphylococcus aureus and the latter is a promising new antibiotic that is not susceptible to the emerging bacterial resistance to vancomycin and teicoplanin. A summary of our recent total synthesis of the vancomycin aglycon, our first and second generation total syntheses of the teicoplanin aglycon, and our progress on the total synthesis of the Ramoplanins is presented. This work lays the foundation for ongoing structure-function studies on the antibiotics that may clarify or define their site and mechanism of action leading to the development of improved or reengineered antibiotics.

  • Functional and biochemical analysis of a key series of Ramoplanin analogues.
    Bioorganic & medicinal chemistry letters, 2009
    Co-Authors: Xiao Fang, Dale L. Boger, Yosup Rew, Dongwoo Shin, Joonwoo Nam, Suzanne Walker
    Abstract:

    Ramoplanin is a potent lipoglycodepsipeptide antibiotic that is active against a wide range of Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococcus (VRE). It acts as an inhibitor of peptidoglycan (PG) biosynthesis that disrupts glycan chain polymerization by binding and sequestering Lipid II, a PG precursor. Herein, we report the functional antimicrobial activity (MIC, S. aureus) and fundamental biochemical assessments against a peptidoglycan glycosyltransferase (Escherichia coli PBP1b) of a set of key alanine scan analogues of Ramoplanin that provide insight into the importance and role of each of its individual amino acid residues.

  • Alanine Scan of [l-Dap2]Ramoplanin A2 Aglycon: Assessment of the Importance of Each Residue
    Journal of the American Chemical Society, 2007
    Co-Authors: Joonwoo Nam, Dongwoo Shin, Yosup Rew, Dale L. Boger
    Abstract:

    In efforts that define the importance of each residue and that identify key regions of the molecule, an alanine scan of the Ramoplanin A2 aglycon, a potent antibiotic that inhibits bacterial cell wall biosynthesis, is detailed. As a consequence of both its increased stability (lactam vs lactone) and its “relative” ease of synthesis, the alanine scan was conducted on [Dap2]Ramoplanin A2 aglycon, which possesses antimicrobial activity equal to or slightly more potent than that of Ramoplanin A2 or its aglycon. Thus, 14 key analogues of the Ramoplanin A2 aglycon, representing a scan of residues 3−13, 15, and 17, were prepared enlisting a convergent solution-phase total synthesis that consolidated the effort to a manageable level. The antimicrobial activity of the resulting library of analogues provides insight into the importance and potential role of each residue of this complex glycopeptide antibiotic.

  • The mechanism of action of Ramoplanin and enduracidin.
    Molecular bioSystems, 2005
    Co-Authors: Xiao Fang, Dale L. Boger, Jutta Wanner, Kittichoat Tiyanont, Yi Zhang, Suzanne Walker
    Abstract:

    The lipoglycodepsipeptide antibiotic Ramoplanin is proposed to inhibit bacterial cell wall biosynthesis by binding to intermediates along the pathway to mature peptidoglycan, which interferes with further enzymatic processing. Two sequential enzymatic steps can be blocked by Ramoplanin, but there is no definitive information about whether one step is inhibited preferentially. Here we use inhibition kinetics and binding assays to assess whether Ramoplanin and the related compound enduracidin have an intrinsic preference for one step over the other. Both Ramoplanin and enduracidin preferentially inhibit the transglycosylation step of peptidoglycan biosynthesis compared with the MurG step. The basis for stronger inhibition is a greater affinity for the transglycosylase substrate Lipid II over the MurG substrate Lipid I. These results provide compelling evidence that Ramoplanin's and enduracidin's primary cellular target is the transglycosylation step of peptidoglycan biosynthesis.

  • Dissecting Ramoplanin: mechanistic analysis of synthetic Ramoplanin analogues as a guide to the design of improved antibiotics.
    Journal of the American Chemical Society, 2004
    Co-Authors: Lan Chen, Jeremiah S. Helm, Dale L. Boger, Yosup Rew, Dongwoo Shin, Yanqiu Yuan, Suzanne Walker
    Abstract:

    Ramoplanin is a potent cyclic lipoglycodepsipeptide antibiotic that disrupts bacterial cell wall synthesis by binding to the peptidoglycan intermediate Lipid II and blocking its polymerization to form the carbohydrate chains of peptidoglycan. Although Ramoplanin is a promising compound for certain indications, it has limitations that impede IV administration for systemic use. However, it may be possible to overcome these limitations with analogues. In this manuscript, we dissect the effects of structural changes to Ramoplanin. The studies described here combine total synthesis with enzyme kinetics, NMR analysis, and MIC measurements to shed light on the roles of key structural features in this antibiotic in Lipid II binding, transglycosylation inhibition, and biological activity. The results should serve as a foundation for the design of synthetically accessible analogues with improved biological properties.

Dewey G. Mccafferty - One of the best experts on this subject based on the ideXlab platform.

  • Discovery of Six Ramoplanin Family Gene Clusters and the Lipoglycodepsipeptide Chersinamycin
    Chembiochem : a European journal of chemical biology, 2020
    Co-Authors: Kelsey T. Morgan, Jeffrey Zheng, Dewey G. Mccafferty
    Abstract:

    Ramoplanins and enduracidins are peptidoglycan lipid intermediate II-binding lipodepsipeptides with broad-spectrum activity against methicillin- and vancomycin-resistant Gram-positive pathogens. Targeted genome mining using probes from conserved sequences within the Ramoplanin/enduracidin biosynthetic gene clusters (BGCs) was used to identify six microorganisms with BGCs predicted to produce unique lipodepsipeptide congeners of Ramoplanin and enduracidin. Fermentation of Micromonospora chersina yielded a novel lipoglycodepsipeptide, called chersinamycin, which exhibited good antibiotic activity against Gram-positive bacteria (1-2 μg/mL) similar to the Ramoplanins and enduracidins. The covalent structure of chersinamycin was determined by NMR spectroscopy and tandem mass spectrometry in conjunction with chemical degradation studies. These six new BGCs and isolation of a new antimicrobial peptide provide much-needed tools to investigate the fundamental aspects of lipodepsipeptide biosynthesis and to facilitate efforts to produce novel antibiotics capable of combating antibiotic-resistant infections.

  • targeted genome mining discovery of the Ramoplanin congener chersinamycin from the dynemicin producer micromonospora chersina dsm 44154
    bioRxiv, 2020
    Co-Authors: Kelsey T. Morgan, Jeffrey Zheng, Dewey G. Mccafferty
    Abstract:

    The availability of genome sequence data combined with bioinformatic genome mining has accelerated the identification of biosynthetic gene clusters (BGCs). Ramoplanins and enduracidins are lipodepsipeptides produced by Actinoplanes Ramoplaninifer ATCC 33076 and Streptomyces fungicidicus B-5477, respectively, that exhibit excellent in vitro activity against a broad spectrum of Gram-positive pathogens. To explore if Ramoplanin/enduracidin-like BGCs exist within genomes of organisms sequenced to date, we devised a targeted genome mining strategy that employed structure-activity relationships to identify conserved, essential biosynthesis genes from the Ramoplanin and enduracidin BGCs. Five microorganisms were found to contain Ramoplanin-like BGCs: the enediyne antibiotic producer Micromonospora chersina strain DSM 44151(dynemycin); the glycopeptide antibiotic producers Amycolatopsis orientalis strain B-37 (norvancomycin), Amycolatopsis orientalis strain DSM 40040 (vancomycin), and Amycolatopsis balhimycina FH1894 strain DSM 44591 (balhimycin); and Streptomyces sp. TLI_053. A single compound from fermentation of M. chersina was purified to homogeneity and found to possess good antibiotic activity against several Gram-positive bacterial test strains (1-2 μg/mL), comparing favorably to Ramoplanin family members. We named this compound chersinamycin and elucidated its covalent structure, which differs distinctly from Ramoplanins and enduracidins. Further, the chersinamycin BGC was validated through insertional gene inactivation using CRISPR-Cas9 gene editing. In addition to the information gained by comparing and contrasting the sequence and organization of these five new BGCs, the amenability of M. chersina to genetic manipulation provides a much-needed tool to investigate the fundamental aspects of lipodepsipeptide biosynthesis and to facilitate metabolic engineering efforts for the production of novel antibiotics capable of combating antibiotic-resistant infections.

  • Functional Analysis of the Lipoglycodepsipeptide
    2015
    Co-Authors: Antibiotic Ramoplanin, Dewey G. Mccafferty
    Abstract:

    select lantibiotics (nisin, epidermin, mersacidin, and ac-tagardine), Ramoplanin captures Lipid I and II. Seques-tration of Lipid I/II by Ramoplanin precludes their normal utilization as substrates by MurG and the transglycosy-lase (TGase) enzymes. As a result, bacteria produce

  • Studies on the biosynthesis of the lipodepsipeptide antibiotic Ramoplanin A2.
    Bioorganic & medicinal chemistry, 2011
    Co-Authors: Amanda J Hoertz, James B Hamburger, David M. Gooden, Maria M. Bednar, Dewey G. Mccafferty
    Abstract:

    Ramoplanin, a non-ribosomally synthesized peptide antibiotic, is highly effective against several drug-resistant Gram-positive bacteria, including vancomycin-resistant Enterococcus faecium (VRE) and methicillin-resistant Staphylococcus aureus (MRSA), two important opportunistic human pathogens. Recently, the biosynthetic cluster from the Ramoplanin producer Actinoplanes ATCC 33076 was sequenced, revealing an unusual architecture of fatty acid and non-ribosomal peptide synthetase biosynthetic genes (NRPSs). The first steps towards understanding how these biosynthetic enzymes cooperatively interact to produce the depsipeptide product are expression and isolation of each enzyme to probe its specificity and function. Here we describe the successful production of soluble enzymes from within the Ramoplanin locus and the confirmation of their specific role in biosynthesis. These methods may be broadly applicable to the production of biosynthetic enzymes from other natural product biosynthetic gene clusters, especially those that have been refractory to production in heterologous hosts despite standard expression optimization methods.

  • Generation of Ramoplanin-resistant Staphylococcus aureus.
    FEMS microbiology letters, 2010
    Co-Authors: John W. Schmidt, Adrienne Greenough, Michelle Burns, Andrea E. Luteran, Dewey G. Mccafferty
    Abstract:

    Ramoplanin is a lipoglycodepsipeptide antimicrobial active against clinically important Gram-positive bacteria including methicillin-resistant Staphylococcus aureus. To proactively examine Ramoplanin resistance, we subjected S. aureus NCTC 8325-4 to serial passage in the presence of increasing concentrations of Ramoplanin, generating the markedly resistant strain RRSA16. Susceptibility testing of RRSA16 revealed the unanticipated acquisition of cross-resistance to vancomycin and nisin. RRSA16 displayed phenotypes, including a thickened cell wall and reduced susceptibility to Triton X-100-induced autolysis, which are associated with vancomycin intermediate-resistant S. aureus strains. Passage of RRSA16 for 18 days in a drug-free medium yielded strain R16-18d with restored antibiotic susceptibility. The RRSA16 isolate may be used to identify the genetic and biochemical basis for Ramoplanin resistance and to further our understanding of the evolution of antibiotic cross-resistance mechanisms in S. aureus.

Lance R. Peterson - One of the best experts on this subject based on the ideXlab platform.

Carol A Kauffman - One of the best experts on this subject based on the ideXlab platform.

  • Therapeutic and preventative options for the management of vancomycin-resistant enterococcal infections.
    Journal of Antimicrobial Chemotherapy, 2003
    Co-Authors: Carol A Kauffman
    Abstract:

    Enterococci are naturally resistant to a wide range of antimicrobial agents. In addition, some enterococci, known as vancomycin-resistant enterococci (VRE) have become resistant to glycopeptide antibiotics. The therapeutic options for VRE infections are therefore very limited. New antimicrobials have been developed that are active against VRE, such as linezolid and quinupristin/dalfopristin. Others, e.g. tigecycline, daptomycin and oritavancin, are in the later stages of development. However, resistance has already been detected to some of these agents. Some success has been enjoyed through the application of older antibiotics against VRE. The lack of therapeutic options has led to the consideration of measures to prevent infection with VRE. In addition to standard infection control procedures such as isolation and hand washing, decolonization of the gastrointestinal tract has been investigated as a method for the prevention of VRE infection in vulnerable patient groups. Several decolonization regimens have been investigated. These include the use of Ramoplanin, a new glycolipodepsipeptide antibiotic that has features that particularly suit it for decolonization. Ramoplanin is not absorbed from the gastrointestinal tract, has potent bactericidal activity against Gram-positive organisms and limited side effects. These features and current clinical evidence suggest that Ramoplanin may have a role in future gastrointestinal decolonization regimens.

  • effective suppression of vancomycin resistant enterococcus species in asymptomatic gastrointestinal carriers by a novel glycolipodepsipeptide Ramoplanin
    Clinical Infectious Diseases, 2001
    Co-Authors: Michael T Wong, Carol A Kauffman, Harold C Standiford, Peter K Linden, Glenn Fort, Henry J Fuchs, Steven B Porter, Richard P Wenzel
    Abstract:

    Nosocomial bloodstream infections due to vancomycin-resistant enterococci (VRE) are associated with increased morbidity rates, mortality rates, and hospitalization costs. Gastrointestinal carriage of VRE is an important risk factor for subsequent infections. This 3-arm, phase II, double-blinded, randomized, multicenter, placebo-controlled study evaluated the safety and efficacy of oral Ramoplanin (a novel, nonabsorbed glycolipodepsipeptide) versus placebo for suppression of gastrointestinal VRE colonization. Sixty-eight patients who were colonized with VRE were enrolled and received 2 daily doses of Ramoplanin (100 mg or 400 mg) or placebo orally for 7 days. The primary end point was the proportion of persons per group from whom VRE were not recovered (VRE-free) on days 7, 14, and 21 after screening. After treatment, VRE-free status was as follows: day 7, none of the 20 patients in the placebo group, and 17 of 21 (P <.001) and 18 of 20 (P <.001) in the 100-mg and 400-mg Ramoplanin groups, respectively; on day 14, 2 of 20 patients in the placebo group, and 6 of 21 (P =.134) and 7 of 17 (P =.028), in the 100-mg and 400-mg Ramoplanin groups, respectively. By day 21, there were no differences between treatment groups. Adverse events were similar for all treatment groups. Ramoplanin was safe and effective in temporarily suppressing gastrointestinal VRE carriage.

  • Effective Suppression of Vancomycin-Resistant Enterococcus Species in Asymptomatic Gastrointestinal Carriers by a Novel Glycolipodepsipeptide, Ramoplanin
    Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2001
    Co-Authors: Michael T Wong, Carol A Kauffman, Harold C Standiford, Peter K Linden, Glenn Fort, Henry J Fuchs, Steven B Porter, Richard P Wenzel
    Abstract:

    Nosocomial bloodstream infections due to vancomycin-resistant enterococci (VRE) are associated with increased morbidity rates, mortality rates, and hospitalization costs. Gastrointestinal carriage of VRE is an important risk factor for subsequent infections. This 3-arm, phase II, double-blinded, randomized, multicenter, placebo-controlled study evaluated the safety and efficacy of oral Ramoplanin (a novel, nonabsorbed glycolipodepsipeptide) versus placebo for suppression of gastrointestinal VRE colonization. Sixty-eight patients who were colonized with VRE were enrolled and received 2 daily doses of Ramoplanin (100 mg or 400 mg) or placebo orally for 7 days. The primary end point was the proportion of persons per group from whom VRE were not recovered (VRE-free) on days 7, 14, and 21 after screening. After treatment, VRE-free status was as follows: day 7, none of the 20 patients in the placebo group, and 17 of 21 (P

R Williams - One of the best experts on this subject based on the ideXlab platform.