Aridicins, novel glycopeptide antibiotics. II. Isolation and characterization.

Abstract

A new antibacterial antibiotic complex, aridicin, was produced by a new genus, Kibdelosporangiun: aridum (SK&F-AAD-216).The individual factors, aridicins A, B and C, were isolated from the fermentation broth by an Amberlite XAD-7 resin extraction and purified by preparative reversed phase HPLC. The aridicins were found to be novel members of the glycopeptide class of antibiotics as exemplified by ristocetin and vancomycin, based on chemical and spectroscopic data, their molecular weights as determined by FAB mass spectrometry (1,786, 1,800 and 1,814), the detection of actinoidinic acid in their acid hydrolysates, and detailed TLC and HPLC comparisons with representative members of this class.The aridicins are a new complex of cell-wall active antibiotics produced by fermentation of a new genus Kibdelosporangium ariduin (SK&F-AAD-216, ATCC 39323), isolated from a soil sample collected near Pima, Arizona1). The antibiotic complex was isolated from fermentation broth by acid precipitation and chromatography on Amberlite XAD-7. The individual components were separated and purified by preparative reversed phase high performance liquid chromatography (HPLC). Chemical characterization of the components indicated that they were novel glycopeptide antibiotics2) related to vancomycin3,4), ristocetin5,6), avoparcin7) and teicoplanin8). In this report the isolation and characterization of aridicins A, B and C are reported. Isolation and PurificationThe antibiotic complex was isolated from the fermentation broth as outlined in Scheme 1. Precipitation at pH 3 and redissolution at pH 7 provided a 10-fold volume reduction with high recovery in the preliminary isolation step. This solution was passed through an Amberlite XAD-7 column and eluted with 60 % acetonitrile -water to yield a crude extract after concentration in vacuo. The overall recovery from broth after these two steps was in excess of 80 % with an accompanying volume reduction of 100-fold. Further purification was effected by preparative reversed phase HPLC. The frequently reported multistep schemes for the purification of polar, water soluble fermentation products often yield products in low recovery and, being limited in capacity, are difficult to scale-up. However, reversed phase HPLC, a useful analytical tool for monitoring antibiotic production, isolation and purification, also has great potential as a preparative tool for isolating and purifying the sesame products, often in one step9,10,11). An analytical HPLC chromatogram of the crude extract is shown in Fig. 1, with the major components indicated by peaks A, B and C. This separation was readily scaled-up to preparative level (Fig. 2) on Whatman Partisil Prep 40 ODS-3 packing (37' 60 Jim) I Present Address: SeaPharm ,

A40926, a new glycopeptide antibiotic with anti-Neisseria activity

“…Any or all of these factors might account for the modest differences in ED50-Although we cannot yet fully account for the unusual activity of A40926 against N. gonorrhoeae, the antibiotic has two structural features which correlate with its longer halflife of elimination (14). One is its net negative charge at neutral pH; in this, A40926 resembles the aridicins (27). The second feature is the lipophilicity conferred by the fatty acid moiety attached to the N-aminoglucuronic acid.…”

“…The acyl groups were nundecanoic acid in PA and A and isododecanoic acid in PB and B. Among the glycopeptides, teicoplanin, aridicins, and kibdellins also contain fatty acid moieties (3,12,27). Another similarity between A40926 and the aridicins was the presence of two carboxylic acid functions which gave these molecules a net negative charge at neutral pH.…”

“…PA and PB, described here for the first time, predominated in the broth; during purification, these two compounds were largely converted to A and B, whose structures have been described recently (31a). One feature of all four factors, which relates them to teicoplanin and some other glycopeptides (aridicins and kibdellins) (3,27,12) while distinguishing them from vancomycin, ristocetin, and others, is the presence of a fatty acid moiety attached to one of the sugars. In terms of biological activity, the most striking difference between the components of the A40926 complex and other glycopeptide antibiotics is their activity against Neisseria gonorrhoeae.…”

Charge and lipophilicity govern the pharmacokinetics of glycopeptide antibiotics

“…These antibiotics differ from vancomycin in that they have a lipid acyl side chain and a net negative charge at neutral pHs the n-decanoyl moiety. Although these analogs differ from aridicin A by one or two additional methylene units, they are remarkably more lipophilic (16). A series of hydrolysis products were generated to alter the charge and lipophilicity of aridicin A (Sitrin et al, submitted).…”

Pharmacokinetics of A40926 in rats after single intravenous and subcutaneous doses

“…The only difference between factors A and B is the length of their fatty acid chains (n-undecanoic acid in A, isododecanoic acid in B). The presence of a glycolipid (also found in teicoplanin and aridicins) appears to be correlated with a longer elimination half-life in animals and humans (5,7). Subcutaneously (s.c.) administered A40926 is effective in curing experimental septicemia, and preliminary data indicated that A40926 has a particularly long half-life in mice (4).…”