Novel Cephalosporins Selectively Active on Nonreplicating Mycobacterium tuberculosis

• Published in: Journal of medicinal chemistry Vol. 59; no. 13; pp. 6027 - 6044
• Main Authors: Gold, Ben, Smith, Robert, Nguyen, Quyen, Roberts, Julia, Ling, Yan, Lopez Quezada, Landys, Somersan, Selin, Warrier, Thulasi, Little, David, Pingle, Maneesh, Zhang, David, Ballinger, Elaine, Zimmerman, Matthew, Dartois, Véronique, Hanson, Paul, Mitscher, Lester A, Porubsky, Patrick, Rogers, Steven, Schoenen, Frank J, Nathan, Carl, Aubé, Jeffrey
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 14.07.2016; Amer Chemical Soc
• Subjects: Animals; Antitubercular Agents - chemistry; Antitubercular Agents - pharmacokinetics; Antitubercular Agents - pharmacology; Cells, Cultured; Cephalosporins - chemistry; Cephalosporins - pharmacokinetics; Cephalosporins - pharmacology; Chemistry, Medicinal; Female; Hep G2 Cells; Humans; Life Sciences & Biomedicine; Macrophages - microbiology; Mice; Mice, Inbred C57BL; Microbial Sensitivity Tests; Microsomes, Liver - metabolism; Mycobacterium tuberculosis - cytology; Mycobacterium tuberculosis - drug effects; Mycobacterium tuberculosis - physiology; Pharmacology & Pharmacy; Science & Technology; Structure-Activity Relationship; Tuberculosis - drug therapy; Tuberculosis - microbiology; DRUG-RESISTANT; CELL-WALL SYNTHESIS; BACTERIAL PERSISTENCE; INTERFERON-GAMMA; SMALL-MOLECULE; NITRIC-OXIDE SYNTHASE; BETA-LACTAM ANTIBIOTICS; INHIBITORS; IDENTIFICATION; PANTOTHENATE AUXOTROPH
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.5b01833

We report two series of novel cephalosporins that are bactericidal to Mycobacterium tuberculosis alone of the pathogens tested, which only kill M. tuberculosis when its replication is halted by conditions resembling those believed to pertain in the host, and whose bactericidal activity is not dependent upon or enhanced by clavulanate, a β-lactamase inhibitor. The two classes of cephalosporins bear an ester or alternatively an oxadiazole isostere at C-2 of the cephalosporin ring system, a position that is almost exclusively a carboxylic acid in clinically used agents in the class. Representatives of the series kill M. tuberculosis within macrophages without toxicity to the macrophages or other mammalian cells.