Antibiotics, ansa-macrolide

Classes of Useful Antibacterial Antibiotics Penicillin Cephalosporin -C Steroid Aminoglycoside Polymyxin Chloramphenicol Cycloserine Tetracycline Macrolide Ansa macrolide Lincomycin Cycloserine Novobiocin... 

Maytansine s ansa macrolide structure shows noteworthy similarities to those of the rifamycins [255], streptovaricins [256], tolypomycins [257], and geldanamycin [258]. The ansamycin antibiotics and their derivatives have aroused considerable interest as antiviral and antimicrobial agents, and as inhibitors of RNA tumor virus reverse transcriptases. 

Fig. 33. The C7N unit of ansa macrolide and mitomycin antibiotics and its origin from the shikimate pathway. Reprinted, with modifications, from Reference 68 with permission of the Federation of European Microbiological Socieites.

In the case at hand, the y-alkoxy-a, j6-unsaturated esters 13, 15, 17, and 19 were treated with lithium dimethylcuprate in the presence of excess TMSCl in THF at —78 °C, producing the adducts 14, 16, 18, and 20 in 95, 85, 83, and 86% yields, respectively (Scheme 9.4). It was thus possible to assemble the acyclic C19-C28 subunit 21 of rifamycin S (12), which represents the longest sequence of contiguous propionate-derived units among the macrolides and ansa antibiotics. The strategy has also successfully been applied to the syntheses of the (all propionate)-derived segments of such natural products as bafilomycin Ai [13], hygrolidin [14], elaiophylin [15], and scytophycin C [16]. 

As a consequence, intramolecular and intermolecular interactions lead to unexpected chemical properties. In particular, those derivatives with lipophilic side chains tend to aggregate and behave like detergents even in dilute solutions. This property should be taken into account, when ansamycins are used at high concentrations in biological systems. The ansamysins do not contain lactone bonds in their ansa ring, which sets them clearly apart from the macrolide antibiotics. 

AnsA Microbial resistance to fluoroquinolones is increasing, and some strains of Streptococcus pneumoniae are now resistant to ciprofloxacin. The mechanism can involve changes in the structure of topoisomerase IV, one of the targets of fluoroquinolones, which inhibit nucleic acid synthesis. Pneumococcal resistance to penicillins is also increasing via changes in penicillin-binding proteins (PBPs). The other mechanisms listed underlie microbial resistance to other antibiotics as follows sulfonamides (choice B), macrolides (choice C), extended-spectrum penicillins (choice D), and beta-lactams (choice E). 

Celmer [200,201] reported a stereochemical and biogenetic model for the lactone ring of macrolide antibiotics such as oleandomycin, erythromycin and leucomycin. On the other hand, the structural similarity between the carbon skeleton (from C-5 to C-14) of the ansa chain of ansamycins, such as the rifamycins and the streptovaricins, and the lactone ring (from C-3 to C-12) of the macrolide antibiotics was also pointed out [1]. 

About 70 naphthalenoid ansamycins have been reported until now. In most of these ansamycins, the ansa part is composed of 17 carbons, like the rifa-mycins, and in other instances the ansa moiety is composed of 23 carbons, like the naphthomycins [1]. Models for the biosynthesis and stereochemistry (Celmer s model), as applied to macrolide antibiotics [2], have been developed for these two types of ansamycins [3]. 

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