Existing macrolides have never shown definitive clinical efficacy in tuberculosis. Recent reports suggest that ribosome methylation is involved in macrolide resistance in Mycobacterium tuberculosis, a mechanism that newer macrolides have been designed to overcome in gram-positive bacteria. Therefore, selected macrolides and ketolides (descladinose) with substitutions at positions 9, 11,12, and 6 were assessed for activity against M. tuberculosis, and those with MICs of <4 M were evaluated for cytotoxicity to Vero cells and J774A.1 macrophages. Several compounds with 9-oxime substitutions or aryl substitutions at position 6 or on 11,12 carbamates or carbazates demonstrated submicromolar MICs. For the three macrolide-ketolide pairs, macrolides demonstrated superior activity. Four compounds with low MICs and low cytotoxicity also effected significant reductions in CFU in infected macrophages. Active compounds were assessed for tolerance and the ability to reduce CFU in the lungs of BALB/c mice in an aerosol infection model. A substituted 11,12 carbazate macrolide demonstrated significant dose-dependent inhibition of M. tuberculosis growth in mice, with a 10-to 20-fold reduction of CFU in lung tissue. Structure-activity relationships, some of which are unique to M. tuberculosis, suggest several synthetic directions for further improvement of antituberculosis activity. This class appears promising for yielding a clinically useful agent for tuberculosis.Tuberculosis (TB) has been recognized as a major public health problem worldwide, exacerbated greatly by the human immunodeficiency virus pandemic. The length and complexity of antibiotic therapy for tuberculosis and the emergence of multidrug-resistant strains make a compelling case for the development of new efficacious anti-TB drugs.The development of new members of classes of established antibiotics, such as the macrolides, which already possess many desirable pharmacological properties, is one approach to rapidly add new drugs to the existing anti-TB armamentarium.Although they are antibiotics of choice for several respiratory pathogens and have demonstrated efficacy in other mycobacterioses, such as leprosy (6,15,17) and Mycobacterium avium (14,26,27) infections, the macrolides developed to date have lacked potency against the tubercle bacillus (24). The clinical use of clarithromycin in treating tuberculosis is limited to multiple-drug-resistant cases in which there are few remaining treatment options (21).The current development goal for macrolides has been primarily to overcome ribosome modification and drug efflux, the major mechanisms of resistance to this antibiotic class (22). Methylation of A2058, located in the peptidyl transferase loop of domain V of the 23S rRNA subunit, by specific methylases (erm) decreases macrolide binding affinity, rendering the organisms resistant to macrolides, lincosamides, and streptogramins, known as the MLS B phenotype (28,29). Macrolides in which the cladinose group is replaced with a keto group (ketolides) avoid efflux-med...
