Tuberculosis (TB) is one of the leading causes of bacterial infectious disease mortality worldwide. New therapeutic strategies are needed to combat drug resistant strains of Mycobacterium tuberculosis (Mtb), the primary etiological agent of tuberculosis (TB). Biotin protein ligase (MtBPL) occupies a key metabolic nodal point in lipid metabolism, which is particularly vulnerable in Mtb as a result of Mtb’s reliance in vivo on lipid degradation for energy and lipid biosynthesis for construction of its unique waxy cell wall. Bio-AMS (1) is a potent and highly selective antitubercular agent, whose mechanism of action is due to inhibition of MtBPL.1,2 Resistance to Bio-AMS is due to overexpression of Rv3406, a type II alkyl sulfatase,3 which oxidizes 1 at C-5′ of the nucleoside (Figure 2) to afford an intermediate hemiaminal 2 that spontaneously disproportionates to yield biotinylated sulfamide 3 and adenosine aldehyde 4.4 We will describe two strategies to prevent Rv3406-catalyzed antibiotic inactivation: 1) replacement of the sulfamide linker with a sulfonamide linker that prevents hemiaminal formation, and 2) sterically blocking oxidation through incorporation of a 5′-methyl group. The syntheses of these compounds along with the impact of the resulting nucleoside modifications on Rv3406 metabolism, MtBPL inhibition, and whole-cell antibacterial activity will be reported. 1. Duckworth, B. P.; Geders, T. W.; Tiwari, D.; Boshoff, H. I.; Sibbald, P. A.; Barry, C. E., III; Schnappinger, D.; Finzel, B. C.; Aldrich, C. C. Bisubstrate Adenylation Inhibitors of Biotin Protein Ligase from Mycobacterium tuberculosis. Chem. Biol. 2011, 18, 1432–1441 2. Bockman, M. R.; Kalinda, A. S.; Petrilli, R. S.; De la Mora-Rey, T.; Tiwari, D.; Liu, F.; Dawadi, S.; Kandakumar, M.; Rhee, K. Y.; Schnappinger, D.; Finzel, B. C.; Aldrich, C. C. Targeting Mycobacterium tuberculosis Biotin Protein Ligase (MtBPL) with Nucleoside-Based Bisubstrate Adenylation Inhibitors. J. Med. Chem. 2015, 58, 7349–7369. 3. Sogi, K. M.; Gartner, Z. J.; Breidenbach, M. A.; Appel, M. J.; Schelle, M. W.; Bertozzi, C. R. Mycobacterium tuberculosis Rv3406 is a Type II Alkyl Sulfatase Capable of Sulfate Scavenging. PLoS One 2013, 8, e65080. 4. Manuscript in preparation

Avoiding antibiotic inactivation in Mycobacterium tuberculosis through strategic nucleoside modification

251st National Meeting (2016)

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