title: In vitro investigation of the antimicrobial activities of novel tetramethylpiperidine-substituted phenazines against Mycobacterium tuberculosis.
abstract: The intra- and extracellular activities of 5 novel tetramethylpiperidine (TMP)-substituted phenazines against Mycobacterium tuberculosis H37Rv (ATCC 27294) were determined and compared with those of clofazimine and rifampicin. Two of these agents, together with clofazimine, were also tested for their activities against drug-resistant strains of M. tuberculosis. Three of the TMP-substituted phenazine compounds were significantly more active than clofazimine against M. tuberculosis, including multidrug-resistant clinical strains of this microbial pathogen, demonstrating a lack of cross-resistance between the riminophenazines and standard anti-tuberculous drugs. Using M. tuberculosis-infected monocyte-derived macrophages, all of the TMP-substituted phenazines were found to possess intracellular activity which was superior to that of both clofazimine and rifampicin. In this model of intracellular bioactivity, the experimental compounds inhibited bacterial growth at concentrations which were approximately 10-fold lower than the corresponding minimal inhibitory concentration values obtained using conventional in vitro sensitivity testing procedures. These results demonstrate that the novel TMP phenazines are active against multidrug-resistant M. tuberculosis strains, and particularly effective intracellularly.
authors.affiliation: Medical Research Council Unit for Inflammation and Immunity, Department of Immunology, Institute for Pathology, Faculty of Medicine, University of Pretoria, South Africa.
authors.forename: C E
authors.initials: CE
authors.lastname: van Rensburg
authors.forename: G K
authors.initials: GK
authors.lastname: Jooné
authors.forename: F A
authors.initials: FA
authors.lastname: Sirgel
authors.forename: N M
authors.initials: NM
authors.lastname: Matlola
authors.forename: J F
authors.initials: JF
authors.lastname: O'Sullivan
mesh_terms: D000904:Antibiotics, Antitubercular / Q000494:pharmacology*; D002991:Clofazimine / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D010619:Phenazines / Q000737:chemistry / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology; D012293:Rifampin / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000904:Antibiotics, Antitubercular; C402675:B 4121; D010619:Phenazines; D010880:Piperidines; D002991:Clofazimine; D012293:Rifampin