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Separation and Detection of Macrolide Antibiotics by HPLC Using VOL. 50 NO. 1 THE JOURNAL OF ANTIBIOTICS 89 Separation and Detection of Macrolide Antibiotics polymers retain a memoryfor the print molecule and by HPLC Using Macrolide-imprinted Synthetic can be used in the HPLCmodefor separation of struc- turally similar substances, and (in case of single en- Polymers as Stationary Phases antiomer imprinting) resolution of the enantiomers of Martin Siemann1", Lars I. Andersson1^ the print species10). Polymerisation of monomers, which are selected for their ability to engage in non-covalent and Klaus Mosbach* interactions with specific functionality of the print Pure and Applied Biochemistry, Chemical Center, molecule, constitutes the key step. Subsequent removal University of Lund, P.O. Box 124, S-221 00 Lund, Sweden of the print molecule exposes sites within the polymer matrix whose chemical and steric topography is defined (Received for publication June 17, 1996) by the print molecule present during its preparation. These memory sites enable the polymer to later rebind Erythromycin and oleandomycin are macrolide anti- the print molecule, in many instances with binding biotics belonging to the erythromycin type and tylosin affinities and specificities approaching those demon- is one of the compoundsof the structurally very related strated by antigen-antibody systemsll;'140. This paper carbomycin family^ (Fig. 1). In particular erythromycin describes the molecular imprinting of some macrolide has, since its discovery in the early 1950s, been one of antibiotics and the use of the resultant polymers as the very widely used antibiotics, useful in the treatment stationary phases with predetermined selectivity in of a variety of infectious deseases2 ~4). Several methods HPLC. for the determination of these antiobitics in plasma and tissue, including microbial test systems5*, radioimmuno- assay6) and liquid chromatography7'8), have been Materials and Methods described. Polymer Preparation Molecular imprinting9) of organic compounds is Polymerswere prepared according to a methodde- increasingly recognised as a facile technique for the scribed previously10). Imprint molecule; 149mg (0.20 preparation of polymeric materials containing recogni- mmol) of erythromycin A, 151mg (0.22mmol) of tion sites of predetermined specificity. The resulting oleandomycin, or 183mg (0.17mmol) of tylosin, 3.96g Fig. 1. Structures according to MERCKINDEX13) of the macrolides antibiotics. Present address: ! Institute ofBiochemical Engineering, University ofStuttgart, Allmandring 3 1 , 70569 Stuttgart, Ciermany. n Astra Pain Control, Pharmaceutical and Analytical R&D,Bioanalytical Chemistry, S-151 85 Sodertalje, Sweden. 90 THE JOURNAL OF ANTIBIOTICS JAN. 1997 of ethylene glycol dimethacrylate and 344mg of analysed, as has been described in previous studies of methacrylic acid were weighed into 20 ml borosilicate test imprinted polymers10). For each compound the retention tubes and dissolved in 6 ml of dried methylene chloride. factor, k', is related to the relative binding affinity of the Ablank polymer was produced by omitting the print compoundto the imprinted polymer. The extent of molecule. The mixtures were cooled on ice, sonicated and retention of a given compoundon a column is, however, sparged with nitrogen for 5 minutes. Fifty mg of azobis- composed of two factors: the specific binding to the (isobutyronitrile) (initiator) was added and the ampoules imprinted sites and non-specific retention due to inter- were placed under a UV-source (366nm) for 16 hours action with the surface of the polymer. Non-specific at 4°C. The bulk polymers were ground in a mechanical interactions could be reduced to a minimumby addition mortar (Retsch, Haan, Germany) and wet-sieved through of small amounts of acetic acid to the eluent10). a 25/mi sieve (Retsch, Haan, Germany). Fines were All polymers showed strongest affinity for the com- removedby repeated sedimentation from acetonitrile and pound that was present during its preparation (Table the polymer particles were finally dried under vacuum. 1). In all instances, other macrolides were less well recognised, i.e. other macrolides eluted earlier than the HPLC Analysis print species. Onthe column packed with oleandomycin Polymer particles were packed into stainless steel MIP, the print molecule was completely separated from columns (200 x 4.6mm) as described in10). In order to mixtures with erythromycin and tylosin, with separation extract the imprint species, the columns were washedon factors (a) of 6.8 and 5.7, respectively. The same is true line with methanol - acetic acid (9 : 1; v/v; 1 liter) and then for erythromycin and tylosin MIPs. On the column with the eluent. Twenty jj\ of 0.1 mMsamples (dissolved packed with erythromycin MIP, erythromycin is more in the eluent) were analysed isocratically at a flow rate strongly retained than oleandomycin and tylosin (a = 5.0 of 1ml/minute. The eluents were: 0.5% acetic acid in and 2.4, respectively). On the tylosin column, a much chloroform (erythromycin polymer); 1%acetic acid in higher retention factor was recorded for tylosin than for chloroform (oleandomycin polymer); 1 %acetic acid in oleandomycin and erythromycin; in this instance a=. methylene chloride (tylosin polymer). Acetone was used 8.2 and 2.9 were obtained. A non-imprinted reference as a void marker. Retention factors were calculated using polymer, made under otherwise identical conditions but k/=(VR-V0)/V0, where VRis the retention volume of by omitting the print molecule, was not able to retain the compound and Vo is the void volume of the system. any of the compoundstested. With the same mobile Separation factor is a^k^/k^, where kj is the retention phase as used for the imprinted columns, all compounds factor recorded for the print species and k'2 is that for eluted with the void (k'=0.0). In all instances, the the second compound. Plate numbers (N), which were increased retention of the imprint species relative to other around 5000m" 1 for all columns, was calculated using compounds is high, indicating a high specificity of each standard chromatographic theory1 2). MIP. In this context, unrelated compounds, such as cyclosporin and rifampicin, eluted with the void (k' = 0.0) Results and Discussion or was slightly retained (k'= 1.0) on the oleandomycin polymer (Table 1), which further demonstrate the Molecular imprinting of macrolide antibiotic struc- specificity of the imprints. The slight retention of tures were done in methacrylic acid-ethylene glycol rifampicin may be explained by some structural dimethacrylate copolymers. The resultant molecularly similarities to the ansa chain of rifampicin to the imprinted polymers (MIPs) were packed into HPLC- macrolide ring of the imprint species. The very high columns and their specific separation abilities were separations obtained make these polymers useful in Table 1. Chromatographic data obtained by HPLCanalysis of imprinted polymers. Imprint molecule Test compound Oleandomycin Erythromycin Oleandomycin 6.8 1.0 1.4 5.0 1.3 8.0 Erythromycin 1.0 6.8 7.0 1.0 3.7 2.7 Tylosin 1.2 5.7 2.9 2.4 10.7 1.0 Erythromycinestolate 1.3 5.2 0.7 10.0 0.3 35.7 Erythr. ethyl-succinate 0.9 7.6 1.7 4.1 0.1 107.0 Erythromycin stearate 2.0 3.4 0.7 10.0 1.0 10.7 Spiramycin 1.2 5.7 2.7 2.6 9.6 1.1 Rifampicin 1.0 6.8 n.d n.d n.d n.d 0.0 0.0 Cyclosporin on oo 0.0 oo Retention factor, k', and separation factor a, were calculated as described in Materials and Methods, n.d.: not determined. VOL.50 NO. 1 THE JOURNAL OF ANTIBIOTICS 91 respective imprinted macrolides and mayeventually be Fig. 2. Separation of a mixture of each 1mg/ml of cyclo- used in a chromatographic modefor analytic purposes sporin, erythromycin and oleandomycin, and 0. 1 mg/ml of or isolation of these antibiotics from fermentation broths. tylosin on the polymer with the imprints against tylosin. References 1) Keller-Schierlein, W.: Chemie der Makrolith-Anti- biotika. Fortschr. Chem. Org. Naturst. 30: 313-460, 1973 2) Washington, J. A. & W. R. Wilson: Erythromycin: A microbial and clinical perspective after 30 years of clinical use (part 1). Mayo Clin. Proc. 60: 189-203, 1985 3) Washington, J. A. & W. R. Wilson: Erythromycin: A microbial and clinical perspective after 30 years of clinical use (part 2). Mayo Clin. Proc. 60: 271-278, 1985 4) Westphal, J. F.; D. Vetter & J. M. Brogard: Hepathic side-effects of antibiotics. J. Antimicrob. Chemother. 33: 387-401, 1994 5) Huck, T. A.; N. Porter & M. E. Bushel: Positive 0 5 10 15 20 25 30 35 40 45 selection of antibiotic-producing soil isolates. J. Gen. Microbiol. 137: 2321 -2329, 1991 volume (ml) 6) Tanaka, Y.; K. Kimura, Y. Komagata, K. Tsuzuki, H. The eluent was methylene chloride containing 1 % acetic Tomada & S. Omura: Radioimmunoassay for eryth- acid at a flow rate of 1 ml/minute. Detection was at 290 nm. romycin derivatives. J. Antibiotics 41: 258 -260, 1988 Note the strong adsorption of tylosin at this wavelength. 7) Khan, K.; J. Paesen, E. Roets & J. Hoogmartens: Analysis of erythromycin A and its metabolites in biological samples by liquid chromatography with chromatographic separations of the imprint species from post-column ion-pair extraction. L. Liquid Chrom. 17: a mixture of antibiotics and related compounds(Fig. 2). 4195-4212, 1994 The data presented here demonstrate the ability of 8) Janecek, M.; M. A. Quilliam, M. R. Bailey & D. H. molecular imprinting to provide an easy access to North: Determination of erythromycin A by liquid stationary phases with high specificity of the desired chromatography and electrochemical detection, with application to salmon tissue. J. Ghromat. Biomed. Appl. macrolide structure. 619: 63-69, 1993 At least in one instance, the polymer was able to detect 9) Mosbach, K.: Molecular imprinting. Trends Biochem. subtle structural differences. On the erythromycin Sci. 19: 9-14, 1994 column, 2'-esters of erythromycin eluted muchearlier 10) Andersson, L.
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