title: SILA-421 activity in vitro against rifampicin-susceptible and rifampicin-resistant Mycobacterium tuberculosis, and in vivo in a murine tuberculosis model.
abstract: Due to the emergence of multidrug-resistant and extensively drug-resistant tuberculosis (TB), there is an urgent need for new TB drugs or for compounds that improve the efficacy of currently used drugs. In this study, time-kill kinetics of SILA-421 as a single drug and in combination with isoniazid (INH), rifampicin (RIF), moxifloxacin (MXF) or amikacin (AMK) against Mycobacterium tuberculosis were assessed. Therapeutic efficacy in vivo in a mouse TB model was also studied. Further in vitro analysis was performed with a RIF-susceptible and RIF-resistant strains of M. tuberculosis. When used as a single drug, SILA-421 in vitro showed concentration-dependent and time-dependent bactericidal activity. SILA-421 also enhanced the activity of INH and RIF, resulting in synergy in the case of INH. Emergence of INH resistance following exposure to INH can be prevented by the addition SILA-421. SILA-421 had no additional value in combination with MXF or AMK. Furthermore, SILA-421 enhanced the activity of RIF towards a RIF-resistant strain and resulted in complete elimination of RIF-resistant mycobacteria. Unfortunately, in mice with TB induced by a Beijing genotype strain, addition of SILA-421 to an isoniazid-rifampicin-pyrazinamide regimen for 13 weeks did not result in enhanced therapeutic efficacy.
authors.affiliation: Erasmus University Medical Center Rotterdam, Department of Medical Microbiology & Infectious Diseases, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands. Electronic address: g.deknegt@erasmusmc.nl.
authors.forename: Gerjo J
authors.initials: GJ
authors.lastname: de Knegt
authors.affiliation: Erasmus University Medical Center Rotterdam, Department of Medical Microbiology & Infectious Diseases, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands.
authors.forename: Irma A J M
authors.initials: IA
authors.lastname: Bakker-Woudenberg
authors.affiliation: National Institute for Public Health and the Environment (RIVM), National Mycobacteria Reference Laboratory, Bilthoven, The Netherlands.
authors.forename: Dick
authors.initials: D
authors.lastname: van Soolingen
authors.affiliation: Radboud University Medical Center, Department of Pharmacy, Nijmegen, The Netherlands.
authors.forename: Rob
authors.initials: R
authors.lastname: Aarnoutse
authors.affiliation: Radboud University Nijmegen Medical Center, University Centre for Chronic Diseases Dekkerswald, Nijmegen, The Netherlands.
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Boeree
authors.affiliation: Erasmus University Medical Center Rotterdam, Department of Medical Microbiology & Infectious Diseases, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands.
authors.forename: Jurriaan E M
authors.initials: JE
authors.lastname: de Steenwinkel
mesh_terms: D000818:Animals; D000995:Antitubercular Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D004195:Disease Models, Animal; D024881:Drug Resistance, Bacterial; D004357:Drug Synergism; D004359:Drug Therapy, Combination / Q000379:methods; D005260:Female; D008807:Mice, Inbred BALB C; D050296:Microbial Viability / Q000187:drug effects; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D010879:Piperazines / Q000494:pharmacology* / Q000627:therapeutic use*; D012293:Rifampin / Q000494:pharmacology; D012833:Siloxanes / Q000494:pharmacology* / Q000627:therapeutic use*; D016896:Treatment Outcome; D014376:Tuberculosis / Q000188:drug therapy*
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; D012293:Rifampin
keywords: Efflux pump inhibitor; Murine TB model; Mycobacterium tuberculosis; Rifampicin resistance; SILA-421