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Novel Cephalosporins Selectively Active on Nonreplicating Mycobacterium tuberculosis.

TitleNovel Cephalosporins Selectively Active on Nonreplicating Mycobacterium tuberculosis.
Publication TypeJournal Article
Year of Publication2016
AuthorsGold B, Smith R, Nguyen Q, Roberts J, Ling Y, Quezada LLopez, Somersan S, Warrier T, Little D, Pingle M, Zhang D, Ballinger E, Zimmerman M, Dartois V, Hanson P, Mitscher LA, Porubsky P, Rogers S, Schoenen FJ, Nathan C, Aubé J
JournalJ Med Chem
Volume59
Issue13
Pagination6027-44
Date Published2016 Jul 14
ISSN1520-4804
KeywordsAnimals, Antitubercular Agents, Cells, Cultured, Cephalosporins, Female, Hep G2 Cells, Humans, Macrophages, Mice, Mice, Inbred C57BL, Microbial Sensitivity Tests, Microsomes, Liver, Mycobacterium tuberculosis, Structure-Activity Relationship, Tuberculosis
Abstract

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.

DOI10.1021/acs.jmedchem.5b01833
Alternate JournalJ. Med. Chem.
PubMed ID27144688
PubMed Central IDPMC4947980
Grant ListU19 AI111143 / AI / NIAID NIH HHS / United States
K08 AI108799 / AI / NIAID NIH HHS / United States
P30 RR030926 / RR / NCRR NIH HHS / United States
U54 HG005031 / HG / NHGRI NIH HHS / United States
P50 GM069663 / GM / NIGMS NIH HHS / United States