Derivatives of Ribosome-Inhibiting Antibiotic Chloramphenicol Inhibit the Biosynthesis of Bacterial Cell Wall

Here, we describe the preparation and evaluation of alpha,beta-unsaturated carbonyl derivatives of the bacterial translation inhibiting antibiotic chloramphenicol (CAM). Compared to the parent antibiotic, two compounds containing alpha,beta-unsaturated ketones (1 and 4) displayed a broader spectrum of activity against a panel of Gram-positive pathogens with a minimum inhibitory concentration range of 2-32 mu g/mL. Interestingly, unlike the parent CAM, these compounds do not inhibit bacterial translation. Microscopic evidence and metabolic labeling of a cell wall peptidoglycan suggested that compounds 1 and 4 caused extensive damage to the envelope of Staphylococcus aureus cells by inhibition of the early stage of cell wall peptidoglycan biosynthesis. Unlike the effect of membrane-disrupting antimicrobial cationic amphiphiles, these compounds did not rapidly permeabilize the bacterial membrane. Like the parent antibiotic CAM, compounds 1 and 4 had a bacteriostatic effect on S. aureus. Both compounds 1 and 4 were cytotoxic to immortalized nucleated mammalian cells; however, neither caused measurable membrane damage to mammalian red blood cells. These data suggest that the reported CAM-derived antimicrobial agents offer a new molecular scaffold for development of novel bacterial cell wall biosynthesis inhibiting antibiotics.