Actin antibiotics

The actin antibiotics, of which several are represented by the structures 1-9, occur in various Streptomyces species (1,2). The structures were elucidated as 32-membered macrocyclic tetraesters. Nonactin itself was isolated in 1955 by Prelog and his co-workers (1) as the first member of the family, and is its lowest homologue and most symmetrical member. All members of the actin family exhibit antimicrobial and antifungal activity, which increase with increasing size of R, and insecticidal activity against mites (3). 

C. difficile history of antibiotic use, advanced age, underlying illness 5-10 days of antibacteria treatment (range 1st day to 10 weeks of antibiotics) mild to severe inflammatory diarrhea toxins A and B monoglucosylation of Rho protein - disruption of actin cytoskeleton —> mucosal disruption. - COX-2 - prostaglandin E2 —> synthesis of inflammatory cytokines... 

Jiang H, Sha SH, Schacht J (2006) Rac/Rho pathway regulates actin depolymerization induced by aminoglycoside antibiotics. J Neurosci Res 83(8) 1544-1551... 

It was the first naturally occurring crown ether, and the earliest for which the antibiotic activity could be traced to its ionophoric properties (4). The actins give one-to-one complexes with many alkali and alkaline earth metal ions, with nonactin showing selectivity in the order NH4+ > K+ = Rb+ > Cs+ > Na+ > Ba2+ (5). The first X-ray crystal structure of an ionophore-metal complex was obtained from the nonactin-potassium thiocyanate complex (6). The potassium is bound by coordination to all four tetrahydrofuran oxygens and to the four ester carbonyl oxygens, which creates overall a "tennis ball seam" conformation to the carbon framework as it wraps around the metal. 

In 1955, Corbaz and coworkers isolated an antibiotic from Streptomyces viridochromogenes and Streptomyces olivochromogenes which was named nonactin. The antibiotic was unusual because it was a neutral, optically inactive solid. In addition to nonactin, three homologs named monactin, dinactin, and triactin were subsequently isolated. This class of antibiotics is called the actins (Fig. 1). 

In contrast to these polyethers, macrocyclic antibiotics such as the actins complex cations by much larger rings which wrap themselves completely around the cation. The wrapping of the ionophore requries complete removal of the solvent shell of the cation, and this solvent stripping was demonstrated experimentally by Prestegard and Chan in NMR studies of nonactin. Because polyether complexation requires at least partial displacement of the solvent shell surrounding the cation, the complex formation is minimized... 

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