Treatment of
tuberculosis (TB) is impaired by the long duration and complexity of
therapy and the rising incidence of drug resistance. There is an urgent need for new agents with improved efficacy, safety, and compatibility with
combination chemotherapies.
Oxazolidinones offer a potential new class of TB drugs, and
linezolid-the only currently approved
oxazolidinone-has proven highly effective against extensively
drug-resistant (
XDR) TB in experimental trials. However, widespread use of
linezolid is prohibited by its significant toxicities.
AZD5847, a novel
oxazolidinone, demonstrates improved in vitro bactericidal activity against both extracellular and intracellular M.
tuberculosis compared to that of
linezolid. Killing kinetics in broth media and in macrophages indicate that the rate and extent of kill obtained with
AZD5847 are superior to those obtained with
linezolid. Moreover, the efficacy of
AZD5847 was additive when tested along with a variety of conventional TB agents, indicating that
AZD5847 may function well in combination
therapies.
AZD5847 appears to function similarly to
linezolid through impairment of the mycobacterial 50S ribosomal subunit. Future studies should be undertaken to further characterize the pharmacodynamics and pharmacokinetics of
AZD5847 in both in vitro and animal models as well is in human clinical trials.