title: The Discovery of 2-Aminobenzimidazoles That Sensitize Mycobacterium smegmatis and M. tuberculosis to β-Lactam Antibiotics in a Pattern Distinct from β-Lactamase Inhibitors.
abstract: A library of 2-aminobenzimidazole derivatives was screened for the ability to suppress β-lactam resistance in Mycobacterium smegmatis. Several non-bactericidal compounds were identified that reversed intrinsic resistance to β-lactam antibiotics in a manner distinct from β-lactamase inhibitors. Activity also translates to M. tuberculosis, with a lead compound from this study potently suppressing carbenicillin resistance in multiple M. tuberculosis strains (including multidrug-resistant strains). Preliminary mechanistic studies revealed that the lead compounds act through a mechanism distinct from that of traditional β-lactamase inhibitors.
authors.affiliation: Department of Chemistry, North Carolina State University, Raleigh, NC, 27695, USA.
authors.forename: T Vu
authors.initials: TV
authors.lastname: Nguyen
authors.affiliation: Current address: Department of Chemistry, High Point University, High Point, NC, 27268, USA.
authors.forename: Meghan S
authors.initials: MS
authors.lastname: Blackledge
authors.affiliation: Department of Chemistry, North Carolina State University, Raleigh, NC, 27695, USA.
authors.forename: Erick A
authors.initials: EA
authors.lastname: Lindsey
authors.affiliation: Department of Chemistry, North Carolina State University, Raleigh, NC, 27695, USA.
authors.forename: Bradley M
authors.initials: BM
authors.lastname: Minrovic
authors.affiliation: Department of Microbiology, Immunology, and Pathology, Colorado State University, Fort Collins, CO, 80523, USA.
authors.forename: David F
authors.initials: DF
authors.lastname: Ackart
authors.affiliation: Department of Microbiology, Immunology, and Pathology, Colorado State University, Fort Collins, CO, 80523, USA.
authors.forename: Albert B
authors.initials: AB
authors.lastname: Jeon
authors.affiliation: Department of Microbiology, Immunology, and Pathology, Colorado State University, Fort Collins, CO, 80523, USA.
authors.forename: Andrés
authors.initials: A
authors.lastname: Obregón-Henao
authors.affiliation: Department of Chemistry, North Carolina State University, Raleigh, NC, 27695, USA.
authors.forename: Roberta J
authors.initials: RJ
authors.lastname: Melander
authors.affiliation: Department of Microbiology, Immunology, and Pathology, Colorado State University, Fort Collins, CO, 80523, USA.
authors.forename: Randall J
authors.initials: RJ
authors.lastname: Basaraba
authors.affiliation: Department of Chemistry, North Carolina State University, Raleigh, NC, 27695, USA.
authors.forename: Christian
authors.initials: C
authors.lastname: Melander
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001562:Benzimidazoles / Q000737:chemistry / Q000494:pharmacology*; D055808:Drug Discovery; D007769:Lactams / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D020102:Mycobacterium smegmatis / Q000187:drug effects* / Q000201:enzymology; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000201:enzymology; D065093:beta-Lactamase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001618:beta-Lactamases / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D001562:Benzimidazoles; D007769:Lactams; D065093:beta-Lactamase Inhibitors; C027391:2-aminobenzimidazole; D001618:beta-Lactamases
keywords: aminobenzimidazoles; antibiotic resistance; medicinal chemistry; tuberculosis