Bactericidal Activity and Mechanism of Action of AZD5847, a Novel Oxazolidinone for Treatment of Tuberculosis
V. Balasubramanian,Suresh Solapure,Harini Iyer,Ambarish Ghosh,Sreevalli Sharma,Parvinder Kaur,R. Deepthi,Venkita Subbulakshmi,V. K. Ramya,Vasanthi Ramachandran,Meenakshi Balganesh,Lindsay Wright,David Melnick,Scott Butler,Vasan K. Sambandamurthy +14 more
TLDR
AZD5847, a novel oxazolidinone, demonstrates improved in vitro bactericidal activity against both extracellular and intracellular M. tuberculosis compared to that of linezolid, and appears to function similarly to lineZolid through impairment of the mycobacterial 50S ribosomal subunit.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.read more
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New agents for the treatment of drug-resistant Mycobacterium tuberculosis
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PET/CT imaging reveals a therapeutic response to oxazolidinones in macaques and humans with tuberculosis
M. Teresa Coleman,Ray Y. Chen,Myungsun Lee,Philana Ling Lin,Lori E. Dodd,Pauline Maiello,Laura E. Via,Young Ran Kim,Gwendolyn A. Marriner,Véronique Dartois,Charles A. Scanga,Christopher Janssen,Jing Wang,Edwin Klein,Sang Nae Cho,Clifton E. Barry,Clifton E. Barry,JoAnne L. Flynn +17 more
TL;DR: PET/CT imaging in macaques and humans with TB shows a beneficial therapeutic response to linezolid and a new oxazolidinone antibiotic, AZD5847, and quantitative changes in PET/CT scans in both nonhuman primates and humans can be used as early surrogate markers of treatment efficacy in tuberculosis.
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Linezolid for treatment of chronic extensively drug-resistant tuberculosis
Myungsun Lee,Jongmin Lee,Matthew W. Carroll,Hongjo Choi,Seonyeong Min,Taeksun Song,Laura E. Via,Lisa C. Goldfeder,Eunhwa Kang,Boyoung Jin,Hyeeun Park,Hyun-Kyung Kwak,Hyun-Chul Kim,Han Seung Jeon,Ina Jeong,Joon Sung Joh,Ray Y. Chen,Kenneth N. Olivier,Pamela A. Shaw,Dean Follmann,Sun Dae Song,Jong Koo Lee,Duk-Hyoung Lee,Cheon Tae Kim,Véronique Dartois,Seung-kyu Park,Sang Nae Cho,Clifton E. Barry +27 more
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