title: The antimicrobial effect of colistin methanesulfonate on Mycobacterium tuberculosis in vitro.
abstract: Polymyxins have previously been described to have activity against Mycobacterium tuberculosis (MTB), but further research was abandoned due to systemic toxicity concerns to achieve the required MIC. Colistin methanesulfonate (CMS), a polymyxin, is well tolerated when inhaled directly into the lungs, resulting in high local concentrations. We report here for the first time, MIC and MBC data for CMS determined by the microtiter Alamar Blue assay (MABA). We also determined how the MIC would be affected by the presence of pulmonary surfactant (PS) and if any synergy with isoniazid (INH) and rifampicin (RIF) exists. The effect of CMS on the ultrastructure of MTB was also determined. The MIC for CMS was 16 mg/L, while the MBC was 256 mg/L. MIC for CMS in PS was antagonised by eight fold. For synergy, indifference was determined while time-kill assays revealed a greater killing effect when CMS was used together with INH. Ultrastructure analysis suggests that the disruption of the outer polysaccharide layer of MTB by CMS may lead to enhanced uptake of INH. Our findings may provide insight for further investigations of CMS against MTB.
authors.affiliation: Department of Internal Medicine, Division of Infectious Diseases, University of Pretoria, Pretoria, South Africa. Electronic address: shane.vontelin.van.breda@gmail.com.
authors.forename: Shane Vontelin
authors.initials: SV
authors.lastname: van Breda
authors.affiliation: Laboratory for Microscopy and Microanalysis, University of Pretoria, Pretoria, South Africa. Electronic address: antoinette.buys@up.ac.za.
authors.forename: Antoinette
authors.initials: A
authors.lastname: Buys
authors.affiliation: Department of Biochemistry, University of Pretoria, Pretoria, South Africa. Electronic address: zeno.apostolides@up.ac.za.
authors.forename: Zeno
authors.initials: Z
authors.lastname: Apostolides
authors.affiliation: Division of Global Health Equity, Brigham & Women's Hospital, Division of Global Health Equity, Boston, USA. Electronic address: enardell@gmail.com.
authors.forename: Edward Anthony
authors.initials: EA
authors.lastname: Nardell
authors.affiliation: Department of Internal Medicine, Division of Infectious Diseases, University of Pretoria, Pretoria, South Africa. Electronic address: anton.stoltz@up.ac.za.
authors.forename: Anton Carel
authors.initials: AC
authors.lastname: Stoltz
mesh_terms: D000995:Antitubercular Agents / Q000737:chemistry / Q000494:pharmacology*; D002473:Cell Wall / Q000187:drug effects / Q000648:ultrastructure; D003091:Colistin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D004357:Drug Synergism; D007538:Isoniazid / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D050296:Microbial Viability / Q000187:drug effects; D046529:Microscopy, Electron, Transmission; D015394:Molecular Structure; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000254:growth & development / Q000648:ultrastructure; D011663:Pulmonary Surfactants / Q000494:pharmacology; D012293:Rifampin / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013997:Time Factors
chemical_list: D000995:Antitubercular Agents; D011663:Pulmonary Surfactants; C004691:colistinmethanesulfonic acid; D007538:Isoniazid; D012293:Rifampin; D003091:Colistin
keywords: Colistin methanesulfonate; Colistin sulfate; Polymyxin; Self-promoted uptake; Tuberculosis