title: SILA 421, an inhibitor of efflux pumps of cancer cells, enhances the killing of intracellular extensively drug-resistant tuberculosis (XDR-TB).
abstract: Multidrug-resistant and extensively drug-resistant tuberculosis (MDR/XDR-TB) are problematic to manage, especially in patients with acquired immune deficiency syndrome (AIDS). There is therefore a dire need for effective anti-MDR/XDR-TB agents. We have previously shown that agents that inhibit the efflux pumps of MDR bacteria and cancer cells also enhance killing of intracellular mycobacteria, possibly by increasing the availability of K(+) and Ca(2+) needed for the activation of lysosomal enzymes of the phagolysosomal unit. In this study, the newly synthesised and recently patented SILA 409 and 421 were tested for in vitro and ex vivo activity against XDR-TB. The minimum inhibitory concentration (MIC) of SILA compounds was determined by the BACTEC 460 TB system. The effect of each compound on the killing activity of human macrophages infected with XDR-TB was determined by exposing the macrophage that had phagocytosed the bacterium to the compounds and assessing the killing activity by colony-forming unit counting. Amongst the two compounds tested, SILA 421 was shown to have in vitro activity against XDR-TB (MIC<3.5mg/L) and to transform non-killing macrophages into effective killers of phagocytosed bacteria, without any cytotoxic activity. Because SILA 421 revealed good in vitro and ex vivo activities and is devoid of any cytotoxic activity, it is a potential candidate as an anti-MDR/XDR-TB drug.
authors.affiliation: Unit of Mycobacteriology, Instituto de Higiene e Medicina Tropical, Universidade Nova de Lisboa (IHMT/UNL), Rua da Junqueira 96, 1349-008 Lisboa, Portugal.
authors.forename: Marta
authors.initials: M
authors.lastname: Martins
authors.forename: Miguel
authors.initials: M
authors.lastname: Viveiros
authors.forename: Jorge
authors.initials: J
authors.lastname: Ramos
authors.forename: Isabel
authors.initials: I
authors.lastname: Couto
authors.forename: Joseph
authors.initials: J
authors.lastname: Molnar
authors.forename: Martin
authors.initials: M
authors.lastname: Boeree
authors.forename: Leonard
authors.initials: L
authors.lastname: Amaral
mesh_terms: D000995:Antitubercular Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D015169:Colony Count, Microbial; D054908:Extensively Drug-Resistant Tuberculosis / Q000382:microbiology*; D006801:Humans; D008264:Macrophages / Q000382:microbiology; D008826:Microbial Sensitivity Tests; D050296:Microbial Viability / Q000187:drug effects*; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000302:isolation & purification; D010879:Piperazines / Q000494:pharmacology*; D012833:Siloxanes / Q000494:pharmacology*
chemical_list: C523096:1,3-dimethyl-1,3-bis(4-fluorophenyl)-1,3-bis(3-(1-(4-butypiperazinyl))propyl)disiloxane; D000995:Antitubercular Agents; D010879:Piperazines; D012833:Siloxanes