their antibiotic effects, but has led to extensive research on chemically modified tetracyclines or CMTs (like incyclinide) for the treatment of rosacea, acne, diabetes and various types of neoplasms. It has been shown that tetracyclines are not only active against broad spectrum of bacteria, but also against viruses, protozoa that lack mitochondria and some noninfectious conditions. The binding of tetracyclines to cellular dsRNA (double stranded RNA) may be an explanation for their wide range of effect. It can also be attributed to the nature of ribosomal protein synthesis pathways among bacteria. Incyclinide was announced to be ineffective for rosacea in September 2007. Several trials have examined modified and unmodified tetracyclines for the treatment of human cancers; of those, very promising results were achieved with CMT-3 for patients with Kaposi Sarcoma. Structure-activity relationship Tetracyclines are composed of a rigid skeleton of 4 fused rings. The rings structure of tetracyclines is divided into an upper modifiable region and a lower non modifiable region. An active tetracycline requires a C10 phenol as well as a C11-C12 keto-enol substructure in conjugation with a 12a-OH group and a C1-C3 diketo substructure. Removal of the dimethylamine group at C4 reduces antibacterial activity. Replacement of the carboxylamine group at C2 results in reduced antibacterial activity but it is possible to add substituents to the amide nitrogen to get more soluble analogs like the prodrug lymecycline. The simplest tetracycline with measurable antibacterial activity is 6-deoxy-6-demethyltetracycline and its structure is often considered to be the minimum pharmacophore for the tetracycle class of antibiotics. C5-C9 can be modified to make derivatives with varying antibacterial activity. Mechanism of resistance Cells can become resistant to tetracycline by enzymatic inactivation of tetracycline, efflux, ribosomal protection, reduced permeability and ribosome mutation. Inactivation is the rarest type of resistance, where NADPH-dependent oxidoreductase, a class of antibiotic destructase, modifies the tetracycline antibiotic at their oxidative soft spot leading to an inactivation of the tetracycline antibiotic. For example, the oxireductase makes a modification on the C11a site of oxytetracycline. Both Mg2+ chelation and ribosome binding are required for the biological activity of oxytetracycline and the modification attenuate the binding, leading to inactivation of the oxytetracycline antibiotic. In the most common mechanism of reaction, efflux, various resistance genes encode a membrane protein that actively pumps tetracycline out of the cell by exchanging a proton for a tetracycline cation complex. This exchange leads to a reduced cytoplasmic concentration of