title: Antibacterial activity of rifamycins for M. smegmatis with comparison of oxidation and binding to tear lipocalin.
abstract: A mutant of Mycobacterium smegmatis is a potential class I model substitute for Mycobacterium tuberculosis. Because not all of the rifamycins have been tested in this organism, we determined bactericidal profiles for the 6 major rifamycin derivatives. The profiles closely mirrored those established for M. tuberculosis. Rifalazil was confirmed to be the most potent rifamycin. Because the tuberculous granuloma presents a harshly oxidizing environment we explored the effects of oxidation on rifamycins. Mass spectrometry confirmed that three of the six major rifamycins showed autoxidation in the presence of trace metals. Oxidation could be monitored by distinctive changes including isosbestic points in the ultraviolet-visible spectrum. Oxidation of rifamycins abrogated anti-mycobacterial activity in M. smegmatis. Protection from autoxidation was conferred by binding susceptible rifamycins to tear lipocalin, a promiscuous lipophilic protein. Rifalazil was not susceptible to autoxidation but was insoluble in aqueous solution. Solubility was enhanced when complexed to tear lipocalin and was accompanied by a spectral red shift. The positive solvatochromism was consistent with robust molecular interaction and binding. Other rifamycins also formed a complex with lipocalin, albeit to a lesser extent. Protection from oxidation and enhancement of solubility with protein binding may have implications for delivery of select rifamycin derivatives.
authors: Department of Ophthalmology, Jules Stein Eye Institute, University of California, Los Angeles, 100 Stein Plaza, Rm. B-279, Los Angeles, CA 90095, USA; Department of Pathology and Laboratory Medicine, Jules Stein Eye Institute, University of California, Los Angeles, 100 Stein Plaza, Rm. B-279, Los Angeles, CA 90095, USA; Division of Molecular Biology, Biocenter, Innsbruck Medical University, Innrain 80-82, A-6020 Innsbruck, Austria.
authors: Tamara
authors: T
authors: Staudinger
authors: Division of Molecular Biology, Biocenter, Innsbruck Medical University, Innrain 80-82, A-6020 Innsbruck, Austria.
authors: Bernhard
authors: B
authors: Redl
authors: Department of Ophthalmology, Jules Stein Eye Institute, University of California, Los Angeles, 100 Stein Plaza, Rm. B-279, Los Angeles, CA 90095, USA; Department of Pathology and Laboratory Medicine, Jules Stein Eye Institute, University of California, Los Angeles, 100 Stein Plaza, Rm. B-279, Los Angeles, CA 90095, USA. Electronic address: bglasgow@mednet.ucla.edu.
authors: Ben J
authors: BJ
authors: Glasgow
mesh_terms: D000995:Antitubercular Agents / Q000737:chemistry / Q000494:pharmacology*; D004926:Escherichia coli / Q000235:genetics / Q000378:metabolism; D057927:Hydrophobic and Hydrophilic Interactions; D007700:Kinetics; D054834:Lipocalins / Q000737:chemistry* / Q000235:genetics; D008826:Microbial Sensitivity Tests; D008954:Models, Biological; D020102:Mycobacterium smegmatis / Q000187:drug effects* / Q000254:growth & development; D009169:Mycobacterium tuberculosis; D010084:Oxidation-Reduction; D011485:Protein Binding; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics; D012294:Rifamycins / Q000737:chemistry / Q000494:pharmacology*; D012995:Solubility; D013329:Structure-Activity Relationship
chemical_list: D000995:Antitubercular Agents; D054834:Lipocalins; D011994:Recombinant Proteins; D012294:Rifamycins; C068980:KRM 1648
keywords: Lipocalin-1; Mycobacteria smegmatis; Oxidation; Rifabutin (PubChem CID: 6323490); Rifalazil; Rifalazil (PubChem CID: 6540558); Rifampin (PubChem CID: 24871024); Rifamycin; Rifamycin S (PubChem CID: 6436726); Rifamycin SV (PubChem CID: 6324616); Rifapentine (PubChem CID: 6323497); Rifaximin (PubChem CID: 6436173); Tear lipocalin