Inhibition of Siderophore Biosynthesis in Mycobacterium tuberculosis with Nucleoside Bisubstrate Analogues: Structure−Activity Relationships of the Nucleobase Domain of 5′-O-[N-(Salicyl)sulfamoyl]adenosine

Abstract

5′-O-[N-(salicyl)sulfamoyl]adenosine (Sal-AMS) is a prototype for a new class of antitubercular agents that inhibit the aryl acid adenylating enzyme (AAAE) known as MbtA involved in biosynthesis of the mycobactins. Herein, we report the structure-based design, synthesis, biochemical, and biological evaluation of a comprehensive and systematic series of analogues, exploring the structureactivity relationship of the purine nucleobase domain of Sal-AMS. Significantly, 2-phenyl-Sal-AMS derivative 26 exhibited exceptionally potent antitubercular activity with an MIC 99 under irondeficient conditions of 0.049 µM while the N-6-cyclopropyl-Sal-AMS 16 led to improved potency and to a 64-enhancement in activity under iron-deficient conditions relative to iron-replete conditions, a phenotype concordant with the designed mechanism of action. The most potent MbtA inhibitors disclosed here display in vitro antitubercular activity superior to most current first line TB drugs, and these compounds are also expected to be useful against a wide range of pathogens that require arylcapped siderphores for virulence.

Analyses of MbtB, MbtE, and MbtF Suggest Revisions to the Mycobactin Biosynthesis Pathway in Mycobacterium tuberculosis

“…The use of salicyl-AMP analogs initially developed by Quadri and Tan (10) and extended by others (28,40) as inhibitors of M. tuberculosis growth provides a template for targeting the A domains of the MBT megasynthase for drug development. The focus on salicyl-AMP analogs to inhibit the function of MbtA was viable because these analogs were unlikely to inhibit host metabolic processes.…”

Comprehensive Spectroscopic, Steady State, and Transient Kinetic Studies of a Representative Siderophore-associated Flavin Monooxygenase

“…Many pathogens, for example, have multiple iron uptake pathways; if one is inhibited, another may or may not compensate. However, recent work demonstrated that Mycobacterium tuberculosis cultures are susceptible to picomolar levels of chemical inhibitors of MbtA, an enzyme catalyzing biosynthesis of the aryl cap of mycobactin siderophores (23)(24)(25). Like Aspergillus sp., mycobacteria have been predicted to depend on variants of the same siderophore for multiple steps in the uptake, internalization, and storage of iron and hence may be especially susceptible to chemical inhibition of mycobactin biosynthesis.…”

Anti-virulence Strategies to Target Bacterial Infections

“…Several attempts were made to identify compounds that prevent siderophore synthesis and transport. A salicylsulfamoyl adenosine and other nucleoside bisubstrate analogous were found to prevent the early step of siderophore synthesis of Yersinia and Mycobacterium (Ferreras et al 2005;Miethke and Marahiel 2007;Neres et al 2008).…”