title: Antitubercular nucleosides that inhibit siderophore biosynthesis: SAR of the glycosyl domain.
abstract: Tuberculosis is the leading cause of infectious disease mortality in the world by a bacterial pathogen. We previously demonstrated that a bisubstrate inhibitor of the adenylation enzyme MbtA, which is responsible for the second step of mycobactin biosynthesis, exhibited potent antitubercular activity. Here we systematically investigate the structure-activity relationships of the bisubstrate inhibitor glycosyl domain resulting in the identification of a carbocyclic analogue that possesses a KIapp value of 2.3 nM and MIC99 values of 1.56 microM against M. tuberculosis H37Rv. The SAR data suggest the intriguing possibility that the bisubstrate inhibitors utilize a transporter for entry across the mycobacterial cell envelope. Additionally, we report improved conditions for the expression of MbtA and biochemical analysis, demonstrating that MbtA follows a random sequential enzyme mechanism for the adenylation half-reaction.
authors.affiliation: Center for Drug Design, Academic Health Center, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Ravindranadh V
authors.initials: RV
authors.lastname: Somu
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Wilson
authors.forename: Eric M
authors.initials: EM
authors.lastname: Bennett
authors.forename: Helena I
authors.initials: HI
authors.lastname: Boshoff
authors.forename: Laura
authors.initials: L
authors.lastname: Celia
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Beck
authors.forename: Clifton E
authors.initials: CE
authors.lastname: Barry
authors.forename: Courtney C
authors.initials: CC
authors.lastname: Aldrich
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000995:Antitubercular Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D002473:Cell Wall / Q000187:drug effects / Q000378:metabolism; D007700:Kinetics; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000201:enzymology; D009705:Nucleosides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017262:Siderophores / Q000096:biosynthesis*; D013329:Structure-Activity Relationship; D013451:Sulfonic Acids / Q000737:chemistry; D014376:Tuberculosis / Q000188:drug therapy*
chemical_list: D000995:Antitubercular Agents; D001426:Bacterial Proteins; D009705:Nucleosides; D017262:Siderophores; D013451:Sulfonic Acids; D000255:Adenosine Triphosphate; C005741:sulfamic acid