Glycylcyclines: a new generation of tetracyclines.

The widespread dissemination of genes encoding tetracycline resistance has limited the utility of the tetracyclines for many clinical indications (Chopra, Hawkey & Hilton, 1992). There are three types of tetracycline resistance mechanisms described (Speer, Shoemaker & Salyers, 1992): 1) efflux, mediated by trans-membrane-spanning proteins, which results in reduction of the intracellular tetracycline concentration mediated by plasmid or chromosomal determinants , are the two major mechanisms of clinical significance. Previous research with older antimicrobial agents rendered less efficacious because of drug resistance, e.g. ampicillin and nalidixic acid, has yielded important new compounds with improved activity and stability to various resistance mechanisms, i.e. amoxycillin/clavulanic acid combination and the fluoroquinolones, respectively. Based on these previous achievements, a programme was initiated at Lederle Laboratories in 1988 to develop a new tetracycline which would be active against organisms harbouring clinically important, tetracycline-resistance mechanisms. The research programme involved a multidisciplinary approach of chemistry, molecular biology, biochemistry and microbiology. A rational database was constructed which incorporated results from a series of biochemical assays coupled with activity against a selected group of bacteria to determine structure/ function properties of the test compounds. Isogenic strains of Escherichia coli and Staphylococcus aureus, in which important tetracycline-resistant determinants were expressed , were used in an initial screening of test compounds. New tetracycline analogues were studied for their activity against tetracycline-sensitive and-resistant Gram-positive and Gram-negative bacteria; uptake across the outer membrane; binding to bacterial ribosomes and inhibition of protein synthesis. Minocycline was chosen as an appropriate starting point for chemical modifications since it has increased antimicrobial activity compared with other existing tetracyclines (Rogalski, 1985). Studies with new analogues reinforced earner observations with the tetracycline structure that changes to the hydrophobic domain could lead to a compound with enhanced activity whereas changes in the hydrophilic domain resulted in loss of activity. Compounds where the D ring was modified were found to have new and interesting antibacterial activity (Figure). Modifications at positions 7, 8 and 9 were prepared and studied (Sum et al., 1994A; Sum, Lee & Tally, 1994a). The first major breakthrough came with the synthesis of the 9-amino series which resulted in activity against S. aureus strains carrying the tet(M) determinant , however, these compounds were unstable under various testing conditions. Subsequently, 9-formamido-minocycline was prepared which also exhibited potent activity against Gram-positive and tet(M) containing strains but poorer activity against some Gram-negative bacteria. Further structure-activity studies led to the preparation of the …