Antitubercular nucleosides that inhibit siderophore biosynthesis: SAR of the glycosyl domain.
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.
Somu
Ravindranadh V
RV
Center for Drug Design, Academic Health Center, University of Minnesota, Minneapolis, MN 55455, USA.
Wilson
Daniel J
DJ
Bennett
Eric M
EM
Boshoff
Helena I
HI
Celia
Laura
L
Beck
Brian J
BJ
Barry
Clifton E
CE
Aldrich
Courtney C
CC
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*
D000995:Antitubercular Agents; D001426:Bacterial Proteins; D009705:Nucleosides; D017262:Siderophores; D013451:Sulfonic Acids; D000255:Adenosine Triphosphate; C005741:sulfamic acid