Macrolide antibiotics generations

Figure 10.35 Stereoselective generation of chiral precursors for the synthesis of the lichen macrolactone (+)-aspicillin and the macrolide antibiotic pentamycin using FruA catalysis.

Fig. 10 Solid phase synthesis of a library of derivatives of third-generation macrolide antibiotics...

Another example of solid phase DOS involves post-modification of the natural product macrolide antibiotic erythromycin (34) [77]. Erythromycin was first converted to analogue 32 which resembles a third generation macrolide antibiotic with high activity against resistant strains (ABT-773, 35), but is attached to solid phase-bound amino acids by reductive amination. Two further reductive amination steps and cleavage from solid support form a library of compounds of type 33 (Fig. 10). 

Inhibition of ATP synthase (energy transfer) reduces proton flow from the inter-membrane space to the matrix, which inhibits electron flow in the respiratory chain. Oligomycin, a macrolide antibiotic, prevents phosphoryl group transfer of ATP synthase. Dicyclohexylcarbodimide (DCCD) binds to and inhibits ATP synthase. Similar to the inhibitors of Complexes I, III, and IV, energy transfer inhibitors cause accumulation of reactive electrons and generate ROS. 

In summary, the enzymes responsible for pikromycin biosynthesis represent powerful tools for the generation of novel macrolide antibiotic compounds with the unique biosynthetic capabilities of the pikromycin PKS and the substrate flexibility of the respective tailoring enzymes. In the next section, we highlight work directed at investigating and exploiting the biosynthetic enzymes encoded by pikA, des, and pikC for the production of ketolide compounds through chemoenzymatic approaches. 

Lewis acidity L Other notable additions to the chiral pool include chiral bicyclic lactams and further chiral sultam derivs., while syntheses with chiral acyl carbanion equivalents, silanes N-acyl-immonium salts and pyran templates are of obvious application, the last-mentioned being adaptable for a reiterative generation of the key polypropionate chain of macrolide antibiotics. Asym. syntheses via organometallics have also been succinctly reviewed" ... 

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