title: Why and how thioridazine in combination with antibiotics to which the infective strain is resistant will cure totally drug-resistant tuberculosis.
abstract: Over a period of 14 years, the authors have studied thioridazine, an old neuroleptic, that has been shown to have in vitro activity against intracellular Mycobacterium tuberculosis, regardless of its antibiotic resistance status, thioridazine cures infected mice of antibiotic-susceptible and multidrug-resistant tuberculosis (TB) infections and, when used in combination with antibiotics used for therapy of TB, renders the organism significantly more susceptible. This article will describe the authors' further work and the mechanisms by which thioridazine alone and in combination with antibiotics cures an extensively drug-resistant infection and why it is expected to cure totally drug-resistant TB infections as well. The concepts presented are entirely new and because they focus on the activation of killing by nonkilling macrophages where M. tuberculosis normally resides during infection, and coupled to the inhibition of efflux pumps which contribute to the antibiotic-resistant status, effective therapy of any antibiotic-resistant TB infection is possible.
authors.affiliation: Institute of Hygiene and Tropical Medicine, Universidade Nova de Lisboa, Rua Junqueira 100, 1349-008 Lisbon, Portugal. lamaral@ihmt.unl.pt
authors.forename: Leonard
authors.initials: L
authors.lastname: Amaral
authors.forename: Joseph
authors.initials: J
authors.lastname: Molnar
mesh_terms: D000818:Animals; D000904:Antibiotics, Antitubercular / Q000627:therapeutic use*; D002746:Chlorpromazine / Q000494:pharmacology; D004341:Drug Evaluation; D024901:Drug Resistance, Multiple, Bacterial; D004359:Drug Therapy, Combination / Q000379:methods; D054908:Extensively Drug-Resistant Tuberculosis / Q000188:drug therapy* / Q000382:microbiology; D006801:Humans; D008264:Macrophages / Q000187:drug effects / Q000382:microbiology; D051379:Mice; D008826:Microbial Sensitivity Tests; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000472:pathogenicity*; D015995:Prevalence; D013881:Thioridazine / Q000627:therapeutic use*
chemical_list: D000904:Antibiotics, Antitubercular; D013881:Thioridazine; D002746:Chlorpromazine