Bactericidal Activity and Mechanism of Action of AZD5847, a Novel Oxazolidinone for Treatment of Tuberculosis

Abstract

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.T uberculosis (TB), caused by Mycobacterium tuberculosis, continues to pose an enormous threat to global public health (1). In 2010, nearly 9 million people were infected with M. tuberculosis and 1.4 million died from the disease (1, 2). While the vast majority of cases of drug-sensitive TB are curable with appropriate drug therapy, rates of treatment success have stagnated due to the long duration and complexity of therapy and the rising incidence of drug resistance (1, 3, 4). Standard TB therapy alone involves four drugs taken for at least 6 months, and treatment for multidrugresistant (MDR) and extensively drug-resistant (XDR) TB requires administration of more toxic antibiotics-including at least one injectable-for durations of 1 to 2 years (5). Often, patients are coinfected with HIV, which further complicates treatment due to deleterious potential drug-drug interactions between TB medications and antiretrovirals (6). Despite the limitations of current treatment options, only one new class of TB drugs has been approved in the past 40 years (7). There is an urgent need for new TB drugs with greater efficacy, reduced toxicities, and improved compatibility with antiretrovirals.Recent evidence demonstrates that linezolid, the only member of the oxazolidinone class of antimicrobials currently on the market, has efficacy against MDR TB (8-11). The potential of linezolid for the treatment of TB is limited due to the incidence of serious adverse effects, including cytopenias, neuropathies, lactic acidosis, and rhabdomyolysis (12, 13). Risk increases with increasing dose and duration, which is particularly problematic, given the typical extended course of chemotherapy for TB. A numbe...

Evaluation of macrolides for possible use against multidrug-resistant Mycobacterium tuberculosis

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Activity of LCB01-0371, a Novel Oxazolidinone, against Mycobacterium abscessus

“…However, recently, another molecular target of the oxazolidinone class was reported in M. tuberculosis. Linezolid, sutezolid, and AZD5847 were found to be resistant to the T460C (Cys154Arg in L3 protein) mutation in the rplC gene in M. tuberculosis (27)(28)(29). Therefore, we further analyzed the molecular targets of LCB01-0371 by sequencing the rplC and rrl genes derived from M. abscessus LCB01-0371R strains.…”

Tuberculosis: Still a Way to go ahead for a Lead- A Review

“…The prime encounter mode of the chemical entity is through the protein synthesis inhibition of the bacilli. Another potent compound of this class, also have come on the timeline with the research investigation effort, is AZD5847 which is highly effective in intracellular bacilli as well as extracellular cells to that of linezolid without showing antagonism effect to the anti-TB regimen dugs which indicates to the development of the moiety, which has specific protein synthesis hindrance activity as the prior mechanism for anti-TB effect [49][50][51][52][53][54][55][56][57].…”