Synthesis and antimicrobial activity of novel globomycin analogues

Kiho, Toshihiro; Nakayama, Mizuka; Yasuda, Kayo; Miyakoshi, Shunichi; Inukai, Masatoshi; Kogen, Hiroshi

doi:10.1016/s0960-894x(03)00432-3

Cited by 25 publications

(15 citation statements)

References 22 publications

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“…Globomycin is mycobactericidal at elevated concentrations but killing is independent of Lsp in M. tuberculosis, suggesting an alternative pathway of inhibition in this bacterium (Banaiee, Jacobs and Ernst 2007). Globomycin analogues have been described that are more potent against proteobacteria and exhibit antibacterial activity against firmicutes (Kiho et al, 2003(Kiho et al, , 2004. A long alkyl side chain, the lipophilic part of the molecule, increases activity and also shows moderate activity against S. aureus.…”

Section: Globomycin-a Specific Inhibitor Of Lspmentioning

confidence: 99%

The molecular mechanism of bacterial lipoprotein modification—How, when and why?

Buddelmeijer¹

2015

FEMS Microbiology Reviews

106

117

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One-sentence summary: This review highlights recent findings on the mechanism by which proteins are lipidated and discusses the enzymes involved, substrate specificities among bacterial species and the role of lipoprotein modification in the biogenesis of the cell envelope. Editor: Mecky Pohlschroder ABSTRACTPosttranslational modification of proteins by lipidation is a common process in biological systems. Lipids provide protein stability, interaction with other membrane components, and in some cases, due to reversibility of the process, a mechanism for regulating protein localization and function. Bacterial lipoproteins possess fatty acids at their amino-termini that are derived from phospholipids, and this lipid moiety anchors the proteins into the membrane. These lipids, as is the case for lipopolysaccharides and lipoteichoic acids, play an important role in signaling of the innate immune system through the interaction with Toll-like receptors. Over the past three years, tremendous progress has been made in understanding the mechanism by which lipoproteins become lipidated. Advanced methodology in mass spectrometry, proteomics and genome-wide analyses allowed precise characterization of lipoprotein modifications and the identification of the enzymes catalyzing the reactions in diverse bacterial species. This review will highlight new findings on bacterial lipoprotein modification with focus on the reaction mechanisms and the role of lipoproteins in cell envelope homeostasis.

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Section: Globomycin-a Specific Inhibitor Of Lspmentioning

confidence: 99%

The molecular mechanism of bacterial lipoprotein modification—How, when and why?

Buddelmeijer¹

2015

FEMS Microbiology Reviews

106

117

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“…Results are representative of three independent experiments. able (21,22). Based on the present data, investigation of SPase II inhibitors deserves more attention, especially since doxycycline is the only choice of antibiotic for HME (54).…”

Section: Discussionmentioning

confidence: 79%

Proteomic Analysis of and Immune Responses toEhrlichia chaffeensisLipoproteins

et al. 2008

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Ehrlichia chaffeensis is an obligately intracellular gram-negative bacterium and is the etiologic agent of human monocytic ehrlichiosis (HME). Although E. chaffeensis induces the generation of several cytokines and chemokines by leukocytes, E. chaffeensis lacks lipopolysaccharide and peptidoglycan. Bioinfomatic analysis of the E. chaffeensis genome, however, predicted genes encoding 15 lipoproteins and 3 posttranslational lipoprotein-processing enzymes. The present study showed that by use of multidimensional liquid chromatography followed by tandem mass spectrometry, all predicted lipoproteins as well as lipoprotein-processing enzymes were expressed by E. chaffeensis cultured in the human promyelocytic leukemia cell line HL-60. Consistent with this observation, a signal peptidase II inhibitor, globomycin, was found to inhibit E. chaffeensis infection and lipoprotein processing in HL-60 cell culture. To study in vivo E. chaffeensis lipoprotein expression and host immune responses to E. chaffeensis lipoproteins, 13 E. chaffeensis lipoprotein genes were cloned into a mammalian expression vector. When the DNA constructs were inoculated into naïve dogs, or when dogs were infected with E. chaffeensis, the animals developed delayed-type hypersensitivity reactions at cutaneous sites of the DNA construct deposition and serum antibodies to these lipoproteins. This is the first demonstration of lipoprotein expression and elicitation of immune responses by a member of the order Rickettsiales. Multiple lipoproteins expressed by E. chaffeensis in vitro and in vivo may play key roles in pathogenesis and immune responses in HME.

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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%

“…Surprisingly, the globomycin synthetic analog containing the longest fatty acid side chain, 30, exhibited also activity against Gram-positive S. aureus strains with MICs ranging from 6.25 to 12.5 g/ml, Table 3. 65,66 On the other hand, derivatives with a modified macrocyclic core exhibited weak or no activity. For example, it was demonstrated that the L-aThr hydroxyl group is not important for activity, but its stereochemistry turned out to be essential.…”

Section: Li-f/fusaricidinsmentioning

confidence: 99%

“…Modifications at the N-Me position caused conformational change in the peptide resulting in a loss of the bacteri- cidal activity. 65,66 This group of natural products is a rare example of antimicrobial agents active against both Gram-positive and Gram-negative bacteria, representing particularly interesting lead structure(s) for the development of novel broad-spectrum antibiotics.…”

Section: Li-f/fusaricidinsmentioning

confidence: 99%

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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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Synthesis and antimicrobial activity of novel globomycin analogues

Cited by 25 publications

References 22 publications

The molecular mechanism of bacterial lipoprotein modification—How, when and why?

The molecular mechanism of bacterial lipoprotein modification—How, when and why?

Proteomic Analysis of and Immune Responses toEhrlichia chaffeensisLipoproteins

Cyclic Lipodepsipeptides in Novel Antimicrobial Drug Discovery

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