In vitro investigation of the antimicrobial activities of novel tetramethylpiperidine-substituted phenazines against Mycobacterium tuberculosis

The intra- and extracellular activities of 5 novel tetramethylpiperidine (T MP)-substituted phenazines against Mycobacterium tuberculosis H37Rv (ATCC 2 7294) were determined and compared with those of clofazimine and rifampicin . Two of these agents, together with clofazimine, were also tested for thei r activities against drug-resistant strains of M. tuberculosis. Three of th e TMP-substituted phenazine compounds were significantly more active than c lofazimine against M. tuberculosis, including multidrug-resistant clinical strains of this microbial pathogen, demonstrating a lack of cross-resistanc e between the riminophenazines and standard anti-tuberculous drugs. Using M . tuberculosis-infected monocyte-derived macrophages, all of the TMP-substi tuted phenazines were found to possess intracellular activity which was sup erior to that of both clofazimine fazimine and rifampicin. In this model of intracellular bioactivity, the experimental compounds inhibited bacterial growth at concentrations which were approximately 10-fold lower than the co rresponding minimal inhibitory concentration values obtained using conventi onal in vitro sensitivity testing procedures. These results demonstrate tha t the novel TMP phenazines are active against multidrug-resistant M. tuberc ulosis strains, and particularly effective intracellularly. Copyright (C) 2 000 S. Karger AG, Basel.