title: Targeting persisters for tuberculosis control.
abstract: Mycobacterial persisters, the survivors from antibiotic exposure, necessitate the lengthy treatment of tuberculosis (TB) and pose a significant challenge for our control of the disease. We suggest that persisters in TB are heterogeneous in nature and comprise various proportions of the population depending on the circumstances; the mechanisms of their formation are complex and may be related to those required for persistence in chronic infection. Results from recent studies implicate multiple pathways for persister formation, including energy production, the stringent response, global regulators, the trans-translation pathway, proteasomal protein degradation, toxin-antitoxin modules, and transporter or efflux mechanisms. A combination of specifically persister-targeted approaches, such as catching them when active and susceptible either by stimulating them to "wake up" or by intermittent drug dosing, the development of new drugs, the use of appropriate drug combinations, and combined chemotherapy and immunotherapy, may be needed for more effective elimination of persisters and better treatment of TB. Variations in levels of persister formation and in host genetics can play a role in the outcome of clinical treatment, and thus, these may entail personalized treatment regimens.
authors.affiliation: Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, USA. yzhang@jhsph.edu
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhang
authors.forename: Wing Wai
authors.initials: WW
authors.lastname: Yew
authors.forename: Michael R
authors.initials: MR
authors.lastname: Barer
mesh_terms: D000995:Antitubercular Agents / Q000008:administration & dosage / Q000627:therapeutic use; D001692:Biological Transport / Q000187:drug effects; D024881:Drug Resistance, Bacterial / Q000235:genetics*; D004734:Energy Metabolism / Q000187:drug effects / Q000502:physiology; D014644:Genetic Variation; D054884:Host-Pathogen Interactions; D006801:Humans; D026901:Membrane Transport Proteins / Q000378:metabolism; D058990:Molecular Targeted Therapy / Q000379:methods*; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000235:genetics* / Q000472:pathogenicity; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects / Q000378:metabolism; D059748:Proteolysis / Q000187:drug effects; D014397:Tuberculosis, Pulmonary / Q000235:genetics / Q000382:microbiology / Q000628:therapy*
chemical_list: D000995:Antitubercular Agents; D026901:Membrane Transport Proteins; D046988:Proteasome Endopeptidase Complex