SILA 421, an inhibitor of efflux pumps of cancer cells, enhances the killing of intracellular extensively drug-resistant tuberculosis (XDR-TB)

Marta Martins, Miguel Viveiros, Jorge Ramos, Isabel Couto, J. Molnár, Martin Boeree, Leonard Amaral

Research output: Contribution to journalArticle

30 Citations (Scopus)

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 Ca2+ 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 <3.5 mg/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.

Original languageEnglish
Pages (from-to)479-482
Number of pages4
JournalInternational Journal of Antimicrobial Agents
Volume33
Issue number5
DOIs
Publication statusPublished - May 2009

Fingerprint

Extensively Drug-Resistant Tuberculosis
Neoplasms
Macrophages
Microbial Sensitivity Tests
Bacteria
Phagocytosis
Enzyme Activation
Mycobacterium
Human Activities
1,3-dimethyl-1,3-bis(4-fluorophenyl)-1,3-bis(3-(1-(4-butypiperazinyl))propyl)disiloxane
Acquired Immunodeficiency Syndrome
Stem Cells
Pharmaceutical Preparations

Keywords

  • Efflux pumps
  • Macrophages
  • MDR-TB
  • SILA compounds
  • XDR-TB

ASJC Scopus subject areas

  • Microbiology (medical)
  • Infectious Diseases
  • Pharmacology (medical)

Cite this

SILA 421, an inhibitor of efflux pumps of cancer cells, enhances the killing of intracellular extensively drug-resistant tuberculosis (XDR-TB). / Martins, Marta; Viveiros, Miguel; Ramos, Jorge; Couto, Isabel; Molnár, J.; Boeree, Martin; Amaral, Leonard.

In: International Journal of Antimicrobial Agents, Vol. 33, No. 5, 05.2009, p. 479-482.

Research output: Contribution to journalArticle

Martins, Marta ; Viveiros, Miguel ; Ramos, Jorge ; Couto, Isabel ; Molnár, J. ; Boeree, Martin ; Amaral, Leonard. / SILA 421, an inhibitor of efflux pumps of cancer cells, enhances the killing of intracellular extensively drug-resistant tuberculosis (XDR-TB). In: International Journal of Antimicrobial Agents. 2009 ; Vol. 33, No. 5. pp. 479-482.
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