Amphomycin

In 1953 Heinemaim, Kaplan, Muir and Hooper isolated a crystalline antibiotic substance from several streptomyces strains. The strain selected for the production of the antibiotic was isolated from soil collected near Syracuse, New York, and called Streptomyces canus. Because of the amphoteric properties, the antibiotic was named amphomycin . It seems that amphomycin is closely related if not identical to crystallomycin . 

Amphomycin is mainly active against gram-positive bacteria, with little or no activity against gram-negative bacteria or yeast . As its sodium salt, amphomycin has definite therapeutic effects against experimental Tr. gambiense and Tr. rhodesiense infections in mice and a curative value for fatal avian spirochetosis in chicks . It has successfully protected mice infected by intraperitoneal inoculation with 100 ISD oi Diplococcus pneumoniae . It has been reported that the antibacterial activity of crystallomycin and amphomycin is lower in the presence of phosphates, but is completely restored after their removal (Table 1.7). 

The calcium salt of amphomycin has a lethal dose (LD50) (Table 1.8) of 120 mg/kg when given intravenously and haemolysis has been observed 

Name Organism Antibiotic spectrum Mol. wt. Amino acids 

Actinomycin S. antibioticus Gram-pos. bacteria, antineoplastic 1,300 alle, Val Sar, Me-Val, Pro, Thr, Me-IIe, Me-AIa, Hypro 

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Fig. 7. Structure of one member of the amphomycin family where Dab = D-erythro-Oc, /5-diaminobutyric acid Dab = L-threo-a, /5-diaminobutyric acid ...

Pip = D-pipecolic acid MeAsp = A -methylaspartic acid. The amphomycin family member having (+)-3-anteisotridecenoic acid is shown not shown is... 

Amphomycin inhibits bacterial ceU wall synthesis at the translocase step by binding to the large isoprenoid Hpid called undecaprenylphosphate (173,174). In eukaryotes, in a similar manner, amphomycin binds to the large isoprenoid Hpid called doHcholphosphate thus blocking the transfer of mannose from its uridinediphosphate derivative to this Hpid (173—177). Amphomycin has been patented for use as a feed additive (178). 

Tharapautic Function Antibiotic Chatnical Name Amphomycin calcium Common Name Glumamicin... 

The process for producing amphomycin comprises cultivating a strain of Streptomyces canus in an aqueous, nutrient-containing carbohydrate solution under submerged aerobic conditions untii substantiai antibacterial activity is Imparted to the solution and then recovering the so-produced amphomycin from the fermentation broth. 

The amphomycin is then converted to the calcium salt with calcium hydroxide. 

In eukaryotic cells, amphomycin inhibits the formation of GlcNAc-PP-Dol, Man-P-Dol, and Glc-P-Dol from their respective nucleotide esters of sugars and Dol-P.134,158,347,348 These reactions have in common the fact that they require manganese ions and Dol-P, but high concentrations of neither the ion nor the lipid phosphate were able to overcome these blocks. The transfer of preformed Man-P-Dol347 (and, pos-... 

At concentrations of amphomycin that completely block the formation of Man-P-Dol, the incorporation ofa-linked D-mannose into lipid-linked oligosaccharides is not completely inhibited.347 As was mentioned in Sections II,2,a and II,2,b, EDTA in vitro and 2-deoxy-2-fluoro-D-glucose in vivo have a similar effect, namely, the formation of a heptasaceharide-lipid, Man5(GlcNAc)2-PP-Dol, is still possible in the absence of Man-P-Dol. The question as to whether these D-man-nosyl residues come directly from GDP-Man is discussed in Section II,2,b. 

Like many other peptide antibiotics—including the lipopeptides A54145, CDA, amphomycin, laspartomycin and friulimicin daptomycin is produced by a nonribosomal peptide synthetase (NRPS) mechanism.3,6,14 It is produced in fermentation by S. roseosporus by feeding decanoic acid, which is incorporated as the fatty acid starter unit. Much has been learned about the biosynthetic process by fermentation feeding studies and by the analysis of the daptomycin biosynthetic genes.3,6,14,15... 

Fig. 19 Structure of friulimicin B and amphomycin A-1437B and FIMR1043 Glycinocins...

All three mannoses appear to be transferred from dolichyl-phosphoryl-mannose (Dol-P-Man). Incorporation of maimose from exogenously added GDP-mannose is blocked by amphomycin [78], which inhibits Dol-P-Man synthesis [79], and is stimulated by addition of Dol-P [63]. Dol-P-Man synthase is absent from Class E Thy-1 mutants [66], however, GPI anchor synthesis can be restored by transfecting the yeast gene for Dol-P-Man synthase into this mutant cell line [80]. These results suggest that mannose is transferred from GDP-mannose to Dol-P before transfer to the glucosaminyl GPI. 

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