Open AccessNovel Cephalosporins Selectively Active on Nonreplicating Mycobacterium tuberculosis
Author(s) -
Ben Gold,
Robert L. Smith,
Quyen Nguyen,
Julia Roberts,
Yan Lv,
Landys Lopez Quezada,
Selin Somersan,
Thulasi Warrier,
David Little,
Maneesh Pingle,
David Zhang,
Elaine Ballinger,
Matthew Zimmerman,
Véronique Dartois,
P. J. Hanson,
Lester A. Mitscher,
Patrick Porubsky,
Steven A. Rogers,
Frank J. Schoenen,
Carl Nathan,
Jeffrey Aubé
Publication year - 2016
Publication title -
journal of medicinal chemistry
Language(s) - Uncategorized
Resource type - Journals
SCImago Journal Rank - 2.01
H-Index - 261
eISSN - 1520-4804
pISSN - 0022-2623
DOI - 10.1021/acs.jmedchem.5b01833
Subject(s) - cephalosporin , mycobacterium tuberculosis , chemistry , tuberculosis , microbiology and biotechnology , antibacterial agent , antibiotics , biochemistry , biology , medicine , pathology
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.