New developments in tetracycline antibiotics: glycylcyclines and tetracycline efflux pump inhibitors.

The tetracyclines, discovered in the 1940s, are a well-established class of antibiotics that still have a role in treating microbial infections in man. However, the widespread emergence of bacterial resistance due to efflux and ribosomal protection mechanisms has severely limited their effectiveness. A new generation of tetracyclines, the glycylcyclines, has been developed to overcome resistance to earlier tetracyclines. One of the new glycylcyclines, 9-t-butylglyclamido-minocycline (GAR-936, tigecycline) is currently undergoing clinical trials. This review considers the current status of glycylcyclines and the possibility that resistance to these agents might arise in the future. Other approaches are also being taken to address the emergence of resistance to tetracyclines. Recently, a number of tetracycline efflux pump inhibitors have been discovered that might be used in combination with earlier tetracyclines to restore their activity against resistant organisms. However, the development of tetracycline efflux pump inhibitors is complicated by the occurrence of several efflux pump sub-families and by the presence of both efflux and ribosomal protection mechanisms in the same organism, especially in naturally occurring, Gram-positive clinical isolates.