title: Thiazomycin, nocathiacin and analogs show strong activity against clinical strains of drug-resistant Mycobacterium tuberculosis.
abstract: Thiazolyl peptides are a class of natural products with potent Gram-positive antibacterial activities. Lack of aqueous solubility precluded this class of compounds from advancing to clinical evaluations. Nocathiacins and thiazomycins are sub-classes of thiazolyl peptides that are endowed with structural features amenable for chemical modifications. Semi-synthetic modifications of nocathiacin led to a series of analogs with improved water solubility, while retaining potency and antibacterial spectrum. We studied the activities of a selection of two natural products (nocathiacin and thiazomycin) as well as seven polar semi-synthetic analogs against twenty clinical strains of Mycobacterium tuberculosis with MDR phenotypes. Two compounds show useful activity against H37Rv strain with MIC values ⩽1 μM, two (⩽0.5 μm) and three (⩽10 μm). These two derivatives showed MIC values ⩽2.5 μm against most of the 20 MDR strains regardless their resistance profile. Specifically, these lack cross-resistance to rifampicin, isoniazid and moxifloxacin.
authors.affiliation: Discovery Chemistry, MRL, Merck & Co., Inc., Kenilworth, NJ, USA.
authors.forename: Sheo B
authors.initials: SB
authors.lastname: Singh
authors.affiliation: Discovery Chemistry, MRL, Merck & Co., Inc., Rahway, NJ, USA.
authors.forename: Libo
authors.initials: L
authors.lastname: Xu
authors.affiliation: Discovery Chemistry, MRL, Merck & Co., Inc., Rahway, NJ, USA.
authors.forename: Peter T
authors.initials: PT
authors.lastname: Meinke
authors.affiliation: Public Health Research Institute, NJMS-Rutgers University, Newark, NJ, USA.
authors.forename: Natalia
authors.initials: N
authors.lastname: Kurepina
authors.affiliation: Public Health Research Institute, NJMS-Rutgers University, Newark, NJ, USA.
authors.forename: Barry N
authors.initials: BN
authors.lastname: Kreiswirth
authors.affiliation: Antibacterial Discovery, MRL, Merck & Co., Inc., West Point, PA, USA.
authors.forename: David B
authors.initials: DB
authors.lastname: Olsen
authors.affiliation: Antibacterial Discovery, MRL, Merck & Co., Inc., Kenilworth, NJ, USA.
authors.forename: Katherine
authors.initials: K
authors.lastname: Young
mesh_terms: D000995:Antitubercular Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D024901:Drug Resistance, Multiple, Bacterial; D024841:Fluoroquinolones / Q000494:pharmacology; D036341:Intercellular Signaling Peptides and Proteins; D007538:Isoniazid / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D000077266:Moxifloxacin; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D010456:Peptides, Cyclic / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D012293:Rifampin / Q000494:pharmacology; D012995:Solubility; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000995:Antitubercular Agents; D024841:Fluoroquinolones; D036341:Intercellular Signaling Peptides and Proteins; D010455:Peptides; D010456:Peptides, Cyclic; D013844:Thiazoles; C463319:nocathiacin I; C525268:thiazomycin; D000077266:Moxifloxacin; D007538:Isoniazid; D012293:Rifampin