EM49, a new peptide antibiotic. IV. The structure of EM49.

Parker, W.; Rathnum, Marlene L.

doi:10.7164/antibiotics.28.379

Cited by 28 publications

(20 citation statements)

References 2 publications

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“…35 The position 4 D-Phe/D-Leu and position 5 L-Phe/L-Leu variations seen across the naturally occurring octapeptins do not appear to noticeably impact antibacterial activity. 20, 30, 54, 59 The recent discovery of octapeptin B 5 which has D-Phe at position 5 instead of L-Leu is fascinating as this is the first example of a polymxyin-like lipopeptide with the order of the D-Phe/D-Leu - L-Leu motif reversed. 38 Octapeptin B 5 showed MICs ranging from 2–8 mg/L against P. aeruginosa, A. baumannii and K. pneumoniae, whereas the MICs for polymyxin B ranged from 0.5–2 mg/L; both lipopeptides were in active against the S. aureus and E. faecalis strains tested (Table 2).…”

Section: Structure Activity Relationshipsmentioning

confidence: 99%

Rediscovering the octapeptins

Velkov

Roberts

2017

Nat. Prod. Rep.

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The decline in the discovery and development of novel antibiotics has resulted in the emergence of bacteria that are resistant to almost all available antibiotics. Currently, polymyxin B and E (colistin) are being used as the last-line therapy against life-threatening infections, unfortunately resistance to polymyxins in both the community and hospital setting is becoming more common. Octapeptins are structurally related non-ribosomal lipopeptide antibiotics that do not exhibit cross-resistance with polymyxins and have a broader spectrum of activity that includes Gram-positive bacteria. This makes them a precious and finite resource for the development of new antibiotics against these problematic polymyxin-resistant Gram-negative pathogens, in particular Pseudomonas aeruginosa, Acinetobacter baumannii and Klebsiella pneumoniae. This review surveys the progress in understanding octapeptin chemistry, mechanisms of antibacterial activity and biosynthesis. With the lack of cross-resistance and their broad antibacterial activity, the octapeptins represent ideal candidates for the development of a new generation of polymyxin-like lipopeptide antibiotics targeting polymyxin-resistant ‘superbugs’.

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Section: Structure Activity Relationshipsmentioning

confidence: 99%

Rediscovering the octapeptins

Velkov

Roberts

2017

Nat. Prod. Rep.

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“…The octapeptins were discovered almost four decades ago as natural products produced by the soil bacteria Bacillus circulans and were given the company compound codes Bu-2470, EM49, 333–25 and Bu-1880 by the then Squibb Institute (Princeton), Bristol-Banyo Research Institute (Tokyo) and Shionogi Research Laboratory (Osaka) (Kato and Shoji, 1980; Konishi, et al, 1983; Meyers, et al, 1973; Meyers, et al, 1973; Meyers, et al, 1976; Meyers, et al, 1974; Parker and Rathnum, 1975; Parker and Rathnum, 1973; Shoji, et al, 1976; Shoji, et al, 1980; Sugawara, et al, 1983). Eventually, a consensus on the nomenclature was reached and these octapeptins were alphabetically designated into four sub-groups, A, B, C, and D, based on minor structural differences in their core scaffold (Meyers, et al, 1976).…”

Section: Introductionmentioning

confidence: 99%

Structure, Function, and Biosynthetic Origin of Octapeptin Antibiotics Active against Extensively Drug-Resistant Gram-Negative Bacteria

Velkov

Gallardo-Godoy

Swarbrick

et al. 2018

Cell Chemical Biology

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Resistance to the last-resort antibiotic colistin is now widespread and new therapeutics are urgently required. We report the first in toto chemical synthesis and pre-clinical evaluation of octapeptins, a class of lipopeptides structurally related to colistin. The octapeptin biosynthetic cluster consisted of three non-ribosomal peptide synthetases (OctA, OctB, and OctC) that produced an amphiphilic antibiotic, octapeptin C4, which was shown to bind to and depolarize membranes. While active against multi-drug resistant (MDR) strains in vitro, octapeptin C4 displayed poor in vivo efficacy, most likely due to high plasma protein binding. Nuclear magnetic resonance solution structures, empirical structure-activity and structure-toxicity models were used to design synthetic octapeptins active against MDR and extensively drug-resistant (XDR) bacteria. The scaffold was then subtly altered to reduce plasma protein binding, while maintaining activity against MDR and XDR bacteria. In vivo efficacy was demonstrated in a murine bacteremia model with a colistin-resistant P. aeruginosa clinical isolate.

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“…Optically active 3-hydroxyalkanoic acids possessing a chain length exceeding ten carbon atoms are structural elements of several natural toxins of plants (Herz and Sharma, 1976), microorganisms (Parker and Rathnum, 1975; and higher animals (Boylan and Scheuer, 1967). Among them, lipid A , bearing the active principle of toxic lipopolysaccharides of gramnegative bacteria (Galanos et al, 1984), has attracted most interest by exhibiting stimulating effects on the biosynthesis of arachidonic acid metabolites (Rietschel ef al., 1980) and several mediator proteins (Berry, 1985).…”

Section: Introductionmentioning

confidence: 98%

Chemoenzymatic Preparation of Optically Active Long-Chain 3-Hydroxyalkanoates

1990

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The synthesis of optically active 3-hydroxyalkanoates of varying chain length (C,,, C,, and C18) was investigated using chemoenzymatic methods. While bakers' yeast mediated reduction of 3oxoalkanoates gave (R)-3-hydroxyalkanoates (e.e. >80%, yield -lo%), both enantiomers were obtained by enzymatic resolution of racemic methyl 3-butanoyloxyalkanoates using Geotrichum candidum lipase with moderate to good optical purity (e.e. 32-92%, yield 4040% for both enantiomers). Lipase-catalysed interesterification, however, was found to proceed with similar enantioselectivity but with slow rate of conversion. the other hand, asymmetric reduction of 3-oxoalkanoates using a chirally modified hydrogenation catalyst led to 3-hydroxy derivatives with better than 80% e.e. (Nakahata et al., 1982). Furthermore, optically pure 3-hydroxyalkanoates were obtained in a six step sequence starting from (R)or (S)-malic acid (Larchevsque and Henrot, 1987).In this study we compare the applicability of different chemoenzymatic methods-i.e. yeast reduction, enzymatic hydrolysis and enzymatic transesterification-for the synthesis of enantiomerically enriched long-chain 3-hydroxyalkanoates with a total chain length of Cl0, C14 and C18 (for a preliminary communication see Feichter, Faber and Griengl, 1989). In addition, a branched derivative was investigated since fatty acids of such type have been found to be constitutents of microbial lipopolysaccharides (Wollenweber et al., 1985). MATERIALS AND METHODS GeneralMelting points were determined on a Tottoli apparatus and are uncorrected. Preparative column chromatography was performed on silica gel 60 (230-400 mesh, Merck) and for TLC Merck silica gel 60 FZ4 plates were used. Compounds were visualized either with UV-light or by spraying with vanilline/conc. H2S04 and heat treatment, GLC-analyses were performed on a Hewlett-Packard 7620A chromatograph (2.2 m X l/8" glass column, 3% OV 225 on Supelcoport 100/120) equipped with an FID. Elemental analyses (C, H) of all novel compounds were within 0.5% of calculated values. Optical rotations ([a13 were measured on a Jasco DIP 370 polarimeter in CHC13 solution. 'H and 19FNMR spectra were recorded on a Bruker MSL 300 (300 and 282MHz, respectively) or a Hitachi-Perkin-Elmer R-24-B (60 MHz) spectrometer in CDC13 solution unless otherwise stated. Chemical shifts are reported from TMS or CFC13 as internal standard in ppm (6-scale) and coupling constants (J) in Hz (s = singlet, d = doublet, t = triplet, m = multiplet). All commercially obtained compounds were used as received except acid chlorides which were distilled prior to use. Crude enzyme preparations were employed without further purification. Lipases A, A-6, AY-30,

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EM49, a new peptide antibiotic. IV. The structure of EM49.

Cited by 28 publications

References 2 publications

Rediscovering the octapeptins

Rediscovering the octapeptins

Structure, Function, and Biosynthetic Origin of Octapeptin Antibiotics Active against Extensively Drug-Resistant Gram-Negative Bacteria

Chemoenzymatic Preparation of Optically Active Long-Chain 3-Hydroxyalkanoates

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