Kinetic Analyses of the Siderophore Biosynthesis Inhibitor Salicyl-AMS and Analogues as MbtA Inhibitors and Antimycobacterial Agents

Abstract

There is a paramount need for expanding the drug armamentarium to counter the growing problem of drug-resistant tuberculosis. Salicyl-AMS, an inhibitor of salicylic acid adenylation enzymes, is a first-in-class antibacterial lead compound for the development of tuberculosis drugs targeting the biosynthesis of salicylic acid-derived siderophores. In this study, we determined the K i of salicyl-AMS for inhibition of the salicylic acid adenylation enzyme MbtA from Mycobacterium tuberculosis (MbtA tb ), designed and synthesized two new salicyl-AMS analogues to probe structure-activity relationships (SAR), and characterized these two analogues alongside salicyl-*

Biosynthesis, Mechanism of Action, and Inhibition of the Enterotoxin Tilimycin Produced by the Opportunistic Pathogen Klebsiella oxytoca

“…The K M for holo-ThdA is commensurate with other values reported for thiolation domains with their cognate adenylation domains; however, the apparent K M values of ATP and 3-hydroxyanthranilic acid are an order of magnitude lower and higher than related substrates with aryl acid adenylation domains, respectively. 36,41,66 Apparent K M values determined for these NRPS adenylation enzymes are strongly affected by the assay utilized (hydroxamate-MesG versus the classical pyrophosphate exchange) as well as substrate concentrations, which could explain the observed discrepancies.…”

The Mycobactin Biosynthesis Pathway: A Prospective Therapeutic Target in the Battle against Tuberculosis

“…In a joint research project between Tan and Quadri et al, two novel Sal-AMS derivatives, Sal-AMSNMe ( 76 ) and Sal-6-MeO-AMSN ( 77 ), were reported. The groups investigated the SARs of the base- and linker-modified nucleotides (Figure ).…”

“…107 Chavadi et al 94 (2011) reported that ΔmbtA, ΔmbtB, ΔmbtC, ΔmbtD, ΔmbtE, ΔmbtF, ΔmbtG, and ΔmbtT mutant Msmeg strains were not able to produce an appreciable amount of mycobactin, indicating the essentiality of Mbt ABCDEFGT NRPS-PKS enzymatic machinery in the biosynthesis of the core scaffold of the mycobactin. Bythrow et al 108 constructed Msmeg ΔEM (deficient of both exochelin and mycobactin gene) which failed to show growth in an iron-limiting environment (GAS media, pH 6.6). Based on these findings, we can conclude that the absence of the mycobactin gene leads to growth inhibition in iron-deficient condition, thereby indicating the significance of the mbt gene.…”

Targeting adenylate-forming enzymes with designed sulfonyladenosine inhibitors

“…22), and pyochelin (not shown), respectively. These potent, tight-binding inhibitors also exhibited activity in cell culture as well as antibacterial efficacy in a mouse model of tuberculosis [171, 172]. However, further preclinical development was hampered by a short pharmacokinetic half-life and dose-limiting toxicity.…”