Martin Rao1, Davide Valentini2, Alimuddin Zumla3, Markus Maeurer4. 1. Division of Therapeutic Immunology (TIM), Department of Laboratory Medicine (LABMED), Karolinska Institutet, Stockholm, Sweden. 2. Division of Therapeutic Immunology (TIM), Department of Laboratory Medicine (LABMED), Karolinska Institutet, Stockholm, Sweden; Centre for Allogeneic Stem Cell Transplantation (CAST), Karolinska University Hospital, Huddinge, Stockholm, Sweden. 3. Division of Infection and Immunity, University College London and the NIHR Biomedical Research Centre at UCL Hospitals NHS Foundation Trust, London, UK. 4. Division of Therapeutic Immunology (TIM), Department of Laboratory Medicine (LABMED), Karolinska Institutet, Stockholm, Sweden; Centre for Allogeneic Stem Cell Transplantation (CAST), Karolinska University Hospital, Huddinge, Stockholm, Sweden. Electronic address: markus.maeurer@fundacaochampalimaud.pt.
Abstract
BACKGROUND: New tuberculosis (TB) drug treatment regimens are urgently needed. This study evaluated the potential of the histone deacetylase inhibitors (HDIs) valproic acid (VPA) and suberoylanilide hydroxamic acid (SAHA) to enhance the effects of first-line anti-TB drugs against intracellular Mycobacterium tuberculosis. METHODS: M. tuberculosis H37Rv cultures were exposed to VPA or SAHA over 6 days, in the presence or absence of isoniazid (INH) and rifampicin (RIF). The efficacy of VPA and SAHA against intracellular M. tuberculosis with and without INH or RIF was tested by treating infected macrophages. Bactericidal activity was assessed by counting mycobacterial colony-forming units (CFU). RESULTS: VPA treatment exhibited superior bactericidal activity to SAHA (2-log CFU reduction), while both HDIs moderately improved the activity of RIF against extracellular M. tuberculosis. The bactericidal effect of VPA against intracellular M. tuberculosis was greater than that of SAHA (1-log CFU reduction) and equalled that of INH (1.5-log CFU reduction). INH/RIF and VPA/SAHA combination treatment inhibited intracellular M. tuberculosis survival in a shorter time span than monotherapy (3days vs. 6 days). CONCLUSIONS: VPA and SAHA have adjunctive potential to World Health Organization-recommended TB treatment regimens. Clinical evaluation of the two drugs with regard to reducing the treatment duration and improving treatment outcomes in TB is warranted.
BACKGROUND: New tuberculosis (TB) drug treatment regimens are urgently needed. This study evaluated the potential of the histone deacetylase inhibitors (HDIs) valproic acid (VPA) and suberoylanilide hydroxamic acid (SAHA) to enhance the effects of first-line anti-TB drugs against intracellular Mycobacterium tuberculosis. METHODS:M. tuberculosis H37Rv cultures were exposed to VPA or SAHA over 6 days, in the presence or absence of isoniazid (INH) and rifampicin (RIF). The efficacy of VPA and SAHA against intracellular M. tuberculosis with and without INH or RIF was tested by treating infected macrophages. Bactericidal activity was assessed by counting mycobacterial colony-forming units (CFU). RESULTS:VPA treatment exhibited superior bactericidal activity to SAHA (2-log CFU reduction), while both HDIs moderately improved the activity of RIF against extracellular M. tuberculosis. The bactericidal effect of VPA against intracellular M. tuberculosis was greater than that of SAHA (1-log CFU reduction) and equalled that of INH (1.5-log CFU reduction). INH/RIF and VPA/SAHA combination treatment inhibited intracellular M. tuberculosis survival in a shorter time span than monotherapy (3days vs. 6 days). CONCLUSIONS:VPA and SAHA have adjunctive potential to World Health Organization-recommended TB treatment regimens. Clinical evaluation of the two drugs with regard to reducing the treatment duration and improving treatment outcomes in TB is warranted.
Authors: Monica Campo; Sarah Heater; Glenna J Peterson; Jason D Simmons; Shawn J Skerrett; Harriet Mayanja-Kizza; Catherine M Stein; W Henry Boom; Thomas R Hawn Journal: Tuberculosis (Edinb) Date: 2021-02-18 Impact factor: 3.131
Authors: Joana R Lérias; Georgia Paraschoudi; Eric de Sousa; João Martins; Carolina Condeço; Nuno Figueiredo; Carlos Carvalho; Ernest Dodoo; Mireia Castillo-Martin; Antonio Beltrán; Dário Ligeiro; Martin Rao; Alimuddin Zumla; Markus Maeurer Journal: Front Cell Dev Biol Date: 2020-01-23
Authors: Steven C Mitini-Nkhoma; Elizabeth T Chimbayo; David T Mzinza; David V Mhango; Aaron P Chirambo; Christine Mandalasi; Agness E Lakudzala; Dumizulu L Tembo; Kondwani C Jambo; Henry C Mwandumba Journal: Front Immunol Date: 2021-06-24 Impact factor: 7.561
Authors: Donal J Cox; Amy M Coleman; Karl M Gogan; James J Phelan; Cilian Ó Maoldomhnaigh; Pádraic J Dunne; Sharee A Basdeo; Joseph Keane Journal: Front Immunol Date: 2020-07-23 Impact factor: 7.561