Macrolide antibiotics chemical structures

Fig. 1 Chemical structures of some of the most important antibiotics used nowadays divided into the most representative families fluoroquinolones, sulfonamides, penicillins, macrolides, and tetracyclines. Another important antibiotic, chloramphenicol, is also shown...

Therapeutic Function Topical antifungal Chemical Name Heptaene macrolide antibiotic Common Name -Structural Formula ... 

Fig. 4.6 Chemical structures of MLSb antibiotics. Macrolides are comprised of a central lactone ring of 14, 15 or 16 atoms, from which extend various sugar groups and functional groups. Lincosamides are comprised of two...

Further antibiotics, mainly derived from actinomycetes, are used for special applications in human and veterinary medicine [20]. These compounds have numerous chemical structures. The macrolides, tetracyclines, aminoglycosides, glycopeptides, and ansamycins for instance are used in antibacterial treatment whereas the anthracyclines reached the market to supplement anticancer chemotherapy. The fairly toxic polyether-type antibiotics are preferably used as anticoccidial agents. Due to the dramatically increasing resistance of clinical important bacterial strains new targets for the discovery of novel types of antibacterial agents are urgently needed. 

Werner, G., Hagenmaier, H., Drautz, H., Baumgartner, A., and Zaehner, H. (1984). Metabolic products of microorganisms. 224. Bafilomycins, a new group of macrolide antibiotics. Production, isolation, chemical structure and biological activity. J. Antibiot. 37, 110-117. 

The 16-membered macrolide antibiotics are generally classified into two large groups, namely, the leucomycin-related family and the tylosin-related family, on the basis of the substitution patterns of their aglycons (Fig. 28) [187]. Interestingly, the leucomycin series, such as leucomycin, josamycin, midecamycin, and spiramycin, have been used clinically for humans, while the tylosin series has been utilized in veterinary medicine. In this section, we describe recent studies on the chemical modification of 16-membered macrolides and their structure-activity relationships. 

Kirst, H. A. (1990). Structure modification of macrolide antibiotics. In Recent Progress in the Chemical Synthesis of Antibiotics (G. Lukacs and M. Ohno, Eds.), pp. 40-63. Springer-Verlag, Heidelberg. 

Rapamycin (sirolimus) is another macrolide antibiotic that possesses potent immunosuppressant activity. Rapamycin has a chemical structure partially similar to that of tacrolimus (Fig. 2). It was first isolated from Streptomyces hygro-scopicus strains found in soil obtained on Rapa Nui (Easter Island), hence the name rapamycin [19, 20]. This compound was initially investigated as an antifungal agent and later found to have immunosuppressive activity [21]. Rapamycin also binds to FKBP, but its immunosuppressive mechanisms are distinct from those of tacrolimus and cyclosporin in that it does not act via the calcineurin pathway [22, 23]. The immunosuppressive effects of rapamycin result from its inhibition of T-cell [23, 24] and B-cell [25] proliferation. The key effect on those cells results from the blocking of the signals of several cytokines (IL-2 and IL-4), leading to interruption of the cell cycle from the G, to the S phase. Unlike tacrolimus, the complex of rapamycin and FKBP-12 does not inhibit the dephosphorylase... 

Fig. 2. Chemical structures of macrolide, lincosamide, and streptogramin type B antibiotics. Mac-rolide antibiotics (M) EM, CAM, AZM, HMR 3647, ABT-773, LM A5, RKM, TL, and YM133. Lin-cosamide antibiotics (L) LCM and CLDM. Streptogramin type B antibiotic (S) mikamycin B.

EM also has a motilin-like stimulating activity on gastrointestinal smooth muscles [39]. Therefore, the inhibitory effect on cytokine expression in human cells summarized here may be a third bioactivity of the macrolide antibiotic. We recently reported that some of these derivatives have inhibitory effect on IL-8 production by human airway epithelial cells [72], These analogues also showed inhibitory action on the activation of NFkB and AP-1 assessed by EMSA (M. Desaki etal., unpublished observations, January 2001). Characterization of the chemical structure responsible for its potential would be important to pursue and further investigation for the molecular mechanism would be necessary for a possible new type of anti-inflammatory agent. 

A second aid to the chemical classification of polyenes is the presence in the antibiotic of either a hexosamine sugar or an aromatic moiety. The presence of sugars is a characteristic of macrolide antibiotics. Polyene hexosamines are similar to the sugars present in the non-polyene macrolides [27]. The structure of polyene hexosamines has been determined and with one exception, the carbohydrate is mycosamine [28—30], the structure of which has been unequivocally established by chemical synthesis [31] as 3-amino-3,6-dideoxy-D-mannopyranose (1). The sugar perosamine, 4-amino4,6-dideoxy-D-mannose (2), an isomer of mycosamine, has been isolated from perimycin [31,32]. 

This concise entry (nine chemical operations from 46) to 4 in enantiomerically pure form convincingly establishes the viability of the approach outlined in Scheme 1 for the asymmetric synthesis of certain key structural subunits that are present in members of the family of macrolide antibiotics. However, an even more compelling case in support of the utility of this strategy is evident from its application to the total synthesis of the antibiotics of the erythromycin class. 

Nowadays, antibiotics are primarily classified according to the mechanism of their action, with similarity of chemical structure as a secondary factor. Penicillin and its derivatives inhibit the formation of bacterial cell walls (Fig. 3.38). Cephalosporins have the same active mechanism. Other compounds are taken up into bacterial DNA to form unstable molecules (quinolones, metronidazole) or inhibit peptide synthesis (tetracychnes, aminoglycosides, macrolides). Some antibiotics (e.g. glycopeptides) exert a complex effect. 

Oleandomycin, a 14-membered ring macrolide antibiotic, was isolated in 1956 from fermentation broths of Streptomyces antibioticus [360]. Some years later, oleandomycin was assigned the structure 340 on the basis of its chemical degradation [361]. Oleandomycin is effective, but less potently, against the same spectrum of bacteria as erythromycin, namely Gram-positive bacteria such as staphylococci, streptococci, and pneumococci. The antimicrobial activity of oleandomycin, when combined with tetracycline, is potentiated. In fact, in such a combination it is sold as an antibacterial agent for upper and lower respiratory tract infection. 

Antibiotics differ widely in their polarities because then-chemical structures are very variable. They are synthesized by various living materials like bacterial strains (such as Streptomyces and Bacillus) and marine sponges. Oka et al., have gathered antibiotics purified by CCC from crude extract and fermentation broth. They have shown that CCC can be successfully applied to the separation of macrolides and of various other antibiotics, including various peptide antibiotics, which are strongly adsorbed to silanol groups on the silica gel used in the stationary... 

Figure 11.17 (a) Chemical structures of macrolide antibiotics (note that erythromycin, ETM, was analyzed as its anhydro form shown, (ETM-H2O)), but tylosin (TLS) was analyzed as the intact protonated molecule. Spiromycin (SPM) was used as the internal standard, (b) Multiple reaction monitoring (MRM) chromatograms of macrolides, each spiked at a concentration of 300ng.L before extraction from 100 mL of influent wastewater from a water reclamation plant. The MRM transitions used for quantitation are shown in each case (the precursor ion for Spiromycin I was the (M+2H) + ion, the others were (M+H)+ ions), and the total ion current (TIC) chromatogram is simply the sum of the three MRM traces. Reproduced from Yang, Anal. Bioanal Chem. 385, 623 (2006), with permission from Springer Science and Business Media. 

Although separation of polyene macrolide antibiotics is difficult, considerable progress has been achieved in their purification by HPLC and in the determination of (heir complex chemical structure by sensitive analytical methods, such as proton magnetic resonance, x-ray, and mass spectrometry. 

Figure 2 Chemical structure and building units of some polyene macrolide antibiotics. (Data from Refs, 2 and 7.) M, indicates mycosamine and Me a methyl group.

Figure 3 Chemical structures of the sugar moieties of polyene macrolide antibiotics.

Venturicidines. Brufani et al. have published full details of their chemical and spectroscopic examinations of the macrolide antibiotics venturicidin A and B from Streptomyces aureofaciens. In combination with an. Y-ray analysis, structures (103a) and (103b) have been determined for the two macrolides. 

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