title: Confinement-Induced Drug-Tolerance in Mycobacteria Mediated by an Efflux Mechanism.
abstract: Tuberculosis (TB) is the world's deadliest curable disease, responsible for an estimated 1.5 million deaths annually. A considerable challenge in controlling this disease is the prolonged multidrug chemotherapy (6 to 9 months) required to overcome drug-tolerant mycobacteria that persist in human tissues, although the same drugs can sterilize genetically identical mycobacteria growing in axenic culture within days. An essential component of TB infection involves intracellular Mycobacterium tuberculosis bacteria that multiply within macrophages and are significantly more tolerant to antibiotics compared to extracellular mycobacteria. To investigate this aspect of human TB, we created a physical cell culture system that mimics confinement of replicating mycobacteria, such as in a macrophage during infection. Using this system, we uncovered an epigenetic drug-tolerance phenotype that appears when mycobacteria are cultured in space-confined bioreactors and disappears in larger volume growth contexts. Efflux mechanisms that are induced in space-confined growth environments contribute to this drug-tolerance phenotype. Therefore, macrophage-induced drug tolerance by mycobacteria may be an effect of confined growth among other macrophage-specific mechanisms.
authors: KwaZulu-Natal Research Institute for Tuberculosis and HIV, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban, 4001, South Africa.
authors: Brilliant B
authors: BB
authors: Luthuli
authors: Dept. of Molecular Microbiology and Immunology, Oregon Health and Sciences University, 3181 S. W. Sam Jackson Park Rd., Mail Code L220, Portland, OR, 97239, United States of America.
authors: Georgiana E
authors: GE
authors: Purdy
authors: KwaZulu-Natal Research Institute for Tuberculosis and HIV, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban, 4001, South Africa.
authors: Frederick K
authors: FK
authors: Balagaddé
mesh_terms: D000995:Antitubercular Agents / Q000378:metabolism / Q000494:pharmacology*; D058491:Bacterial Load; D001692:Biological Transport; D002934:Cinnamates / Q000378:metabolism / Q000494:pharmacology; D004058:Diffusion; D004129:Dimethylpolysiloxanes; D004361:Drug Tolerance / Q000235:genetics*; D044127:Epigenesis, Genetic; D006801:Humans; D006921:Hygromycin B / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D007538:Isoniazid / Q000378:metabolism / Q000494:pharmacology; D056656:Lab-On-A-Chip Devices; D008264:Macrophages / Q000382:microbiology; D017551:Microdialysis; D008954:Models, Biological; D020102:Mycobacterium smegmatis / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000235:genetics / Q000254:growth & development; D015242:Ofloxacin / Q000378:metabolism / Q000494:pharmacology; D010641:Phenotype; D012293:Rifampin / Q000378:metabolism / Q000494:pharmacology
chemical_list: D000995:Antitubercular Agents; D002934:Cinnamates; D004129:Dimethylpolysiloxanes; D006921:Hygromycin B; C026273:hygromycin A; C013830:baysilon; D015242:Ofloxacin; D007538:Isoniazid; D012293:Rifampin