Izenamicins: Macrolide antibiotics.

Imai, Harumitsu; Suzuki, Kenichi; Morioka, Moto; Sasaki, Tomohiro; Tanaka, Kouichi R.; Kadota, Shigenobu; Iwanami, Masaru; Saito, Takeshi; Eiki, Hideo

doi:10.7164/antibiotics.42.1000

“…Unfortunately,w ec ould not reproduce the production of 2 in the wild-type strain under any of the fermentation conditions tested, and thus could not positively link its biosynthesis to the spr locus.W ed id, however, observe the loss of five additional compounds in the spr mutant neverb efore reported from this bacterium ( Figure 1A). Upon isolation and complete spectrala nalysis, compounds were found to be the known rosamicin analogues 3 and 21-hydroxyrosamicin (izenamicin A3, [9] 5)a longw ith three new derivatives, 18-dihydro-14-hydroxyrosamicin (6), 18-dihydro-21hydroxyrosamicin (7), and 14-hydroxyrosamicin (8). We predict that the conserveds tereocentersi nt he new rosamicin analogues 6-8 are identicalt ot hose previously reported for 3 and that the new C14 tertiary hydroxy stereocenter in 6 and 8 is S, as in the macrolide mycinamicin II.…”

mentioning

confidence: 99%

“…Detailed HPLC-MS analyses revealed that the mutantn o longerproduced the rosamicin octaketides 3, 5-8,but retained 1 and 4,a lbeit at lower production titers ( Figure 1A). The spr10-Y1290F mutant also produced an ew product, 18-deoxo-5-deoxy-5-oxotylonolide (9), in which the desosamine sugar, the C12-C13 epoxide, and the C18 hydroxy groups werem issing, thus suggestingt hat 9 is not as ubstratef or post-PKS modifying enzymes. We furtheridentified two new compounds with the same molecular composition as 2,a nd the epimeric pacificanone B( Figure S3), yet due to poor production yields, we were unable to conclusively elucidate their structures.…”

mentioning

confidence: 99%

Salinipyrone and Pacificanone Are Biosynthetic By‐products of the Rosamicin Polyketide Synthase

Awakawa

¹

,

Crüsemann

²

,

Munguia

³

et al. 2015

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Salinipyrones and pacificanones are structurally related polyketides from Salinispora pacifica CNS-237 proposed to arise from the same modular polyketide synthase (PKS) assembly line. Genome sequencing revealed a large macrolide PKS gene cluster that codes for the biosynthesis of rosamicin A and a series of new macrolide antibiotics. Mutagenesis experiments unexpectedly correlated salinipyrone and pacificanone biosynthesis to the rosamicin octamodule Spr PKS. Remarkably, this bifurcated polyketide pathway illuminates a series of enzymatic domain and module skipping reactions that dictate natural polyketide product diversity. Our findings enlarge the growing knowledge of polyketide biochemistry and illuminate potential challenges in PKS bioengineering.

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“…Only izenamicin B3 (12) showed potent antibacterial effects against a panel of Grampositive and Gram-negative pathogenic bacteria. 29 From a soil strain M. chalea, a group of seven 16-membered macrolide antibiotics structurally close to rosamicin (7) were reported as juvenimicins A1-A4 (14-17) and juvenimicin B1-B3 (18)(19)(20). They demonstrated antibacterial activity against Gram-positive bacteria, particularly juvenimicin A3 (16) which was the most potent one (MIC 0.1-0.3 mg mL À1 ).…”

Section: Macrolidesmentioning

confidence: 99%

“…[31][32][33] Later in 1998, it was found that rustamicin (18) and its congeners mediate their fungicidal activity via inhibition of the fungal inositol phosphoceramide synthase resulting in interrupted sphingolipid biosynthesis. 34 In 1980, further eighteen compounds called mycinamicin I-XVIII (26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43) were added to the 16-membered macrolide antibiotics family from a soil derived-M. griseorubida strain. Interestingly, mycinamicins showed potent bacteriostatic activity against Gram-positive pathogenic bacteria (MIC 0.1-3.12 mg mL À1 ).…”

Section: Macrolidesmentioning

confidence: 99%

“…Interestingly, mycinamicins showed potent bacteriostatic activity against Gram-positive pathogenic bacteria (MIC 0.1-3.12 mg mL À1 ). 35,36 Aer eight years, both mycinamicin IV (29) and VII (32) were synthesized. 37 Later, a biosynthetic pathway for this class of macrolides was proposed depending on the several biosynthetic intermediates that were isolated, particularly mycinonic acid (44), in addition to many of bioconversion studies.…”

Section: Macrolidesmentioning

confidence: 99%

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The genus Micromonospora as a model microorganism for bioactive natural product discovery

Hifnawy

¹

,

Fouda

²

,

Sayed

³

et al. 2020

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Macrolides

Kirst¹

2000

Kirk-Othmer Encyclopedia of Chemical Technology

0

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Macrolide antibiotics are well‐established antimicrobial agents in both clinical and veterinary medicine. These agents can be administered orally and are generally used to treat infections in the respiratory tract, skin and soft tissues, and genital tract caused by gram‐positive organisms, Mycoplasma species, and certain susceptible gram‐negative and anaerobic bacteria. The macrolide class is large and structurally diverse. Macrolides are produced by fermentation of soil microorganisms. Additionally, structural modifications using both chemical and microbiological means have yielded biologically active semisynthetic derivatives. The term macrolide was introduced to denote the class of substances produced by Streptomyces species containing a macrocyclic lactone ring. Traditional macrolide antibiotics are divided into three families according to the size of the aglycone, which can be 12‐, 14‐, or 16‐membered. Naturally occurring 14‐membered macrolides include erythromycin A (C 37 H 67 NO 13 ), erythromycin B (C 37 H 67 NO 12 ), erythromycin C (C 36 H 65 NO 13 ), erythromycin D (C 36 H 65 NO 12 ), erythromycin F (C 37 H 67 NO 14 ), and erythromycin E (C 37 H 65 NO 14 ), as well as others. Erythromycin has been the principal subject of modification of 14‐membered macrolides; some of the derivatives of erythromycin and oleandomycin include 2′‐ O ‐acetylerythromycin (C 39 H 69 NO 14 ), 2′‐ O ‐propionylerythromycin (C 40 H 71 NO 14 ), erythromycin ethyl carbonate (C 40 H 71 NO 15 ), and others. 16‐Membered macrolides are divided into leucomycin‐ and tylosin‐related groups, which differ in the substitution pattern of their aglycones. Natural products include leucomycin A 1 (C 40 H 67 NO 14 ), leucomycin A 5 (C 39 H 65 NO 14 ), leucomycin A 7 (C 38 H 63 NO 14 ), midecamycin A 2 (C 42 H 69 NO 15 ), and others. A second large group of 16‐membered macrolides differs from the leucomycins in the substitution pattern of the aglycone. One difference is a methyl or hydroxymethyl group at C‐14. The most prominent member of this group is tylosin, an important veterinary antibiotic produced by S. fradiae. Tylosin and related products include tylosin (C 46 H 77 NO 17 ), relomycin (20‐dihydrotylosin) (C 46 H 79 NO 17 ), macrocin (C 45 H 75 NO 17 ), O ‐demethylmacrocin (C 44 H 73 NO 17 ), and others. Other macrolides have been made by chemical, bioconversion, or genetic manipulations which represent hybrids of structures within the 14‐membered family, within the 16‐membered family, or between the two families. The advent of molecular biology has opened new possibilities for producing hybrid macrolides. Genetic manipulations of biosynthetic pathways in macrolide‐producing microorganisms complement traditional chemical and microbiological approaches. Macrolides inhibit growth of gram‐positive bacteria, Mycoplasma species, and certain gram‐negative and anaerobic bacteria. Susceptible gram‐positive bacteria include many species of Staphylococcus and Streptococcus; susceptible gram‐negative bacteria include Bordetella pertussis, Legionella pneumophila, Moraxella catarrhalis (formerly Branhamella ), and Haemophilus ducreyi. Macrolides inhibit growth of bacteria by inhibiting protein synthesis on ribosomes. Bacterial resistance to macrolides is often accompanied by cross‐resistance to lincosamide and streptogramin B antibiotics (MLS‐resistance). Bacterial resistance to antibiotics usually results from modification of a target site, enzymatic inactivation, or reduced uptake into or increased efflux from bacterial cells. The principal side effects of macrolides are gastrointestinal problems, such as pain, indigestion, diarrhea, nausea, and vomiting. Macrolides are obtained by controlled submerged aerobic fermentations of soil microorganisms. Although species of Streptomyces have dominated, species of Saccharopolyspora, Micromonospora, and Streptoverticillium are also well represented. Macrolide antibiotics are used clinically to treat infections resulting from susceptible organisms in the upper and lower respiratory tract, skin and soft tissues, and genital tract. They are generally used orally, although they can be given intravenously. Macrolides are regarded as among the safest of antibiotics. Relatively few macrolides are used in veterinary medicine. The most important is tylosin (Tylan, Elanco Products), which is used to control chronic respiratory disease caused by Mycoplasma gallisepticum in poultry.

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Izenamicins: Macrolide antibiotics.

Abstract: In the course of screening for new antibiotics produced by Micromonospora, we discovered a series of 16-membered macrolide antibiotics, designated as izenamicins, produced by strain YS-02930K. The antibiotics were found to con

Cited by 13 publications

References 4 publications

Salinipyrone and Pacificanone Are Biosynthetic By‐products of the Rosamicin Polyketide Synthase

Salinipyrone and Pacificanone Are Biosynthetic By‐products of the Rosamicin Polyketide Synthase

The genus Micromonospora as a model microorganism for bioactive natural product discovery

Macrolides

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