Preclinical development of α-aminooxyhydroxamic acid derivatives targeting drug-resistant Mycobacterium tuberculosis
Final Report Abstract
The emergence of multidrug-resistant strains of Mycobacterium tuberculosis remains a public health challenge and exacerbates the treatment of tuberculosis (TB). Therefore, there is an urgent need to uncover new anti-TB compounds with unprecedented targets and mode-of-action. This study introduces novel α-aminooxyacetic acid-based antimycobacterial molecules, for which we established straight-forward and flexible synthesis routes. The lead compounds KSK-104 and KSK-106 displayed potent sub-micromolar antibacterial activity against M. tuberculosis XDR clinical isolates, while exhibiting virtually no cytotoxicity against various human cells. Complementation experiments following whole genome sequencing of spontaneously resistant mutants suggested that these compounds are pro-drugs that are intracellularly hydrolyzed by one or both of two specific amidohydrolases, Rv0552 and AmiC. Furthermore, proteomic and transcriptomic analyses of stressed cells and genetic interaction mapping employing transposon insertion sequencing suggest a “dirty drug” mechanism that involves the simultaneous attack of the various drug cleavage products on multiple intracellular targets. Our results suggest a role of the pyridoxal 5’-phosphate (PLP) synthesis and salvage pathways and/or PLP-dependent enzymes, the oxidative stress network, and a misled upregulation of the Rv3092c-Rv3095 gene cluster in the mode of action.
Publications
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α-Aminooxyacetic acid derivatives acting as pro-drugs against Mycobacterium tuberculosis.
Vill, Kristin; van Geelen, Lasse; Michel, Oliver; Kiffe-Delf, Anna-Lene; Berger, Alexander; Podlesainski, David; Stenzel, Katharina; Kovacic, Filip; Lungerich, Beate; Burkhardt, Björn; Crooks, Taylor A.; Howe, Michael D.; Ostrer, Lev; Jia, Ziyi; Ioerger, Thomas R.; Kaschani, Farnusch; Kaiser, Markus; Baughn, Anthony D.; Kurz, Thomas & Kalscheuer, Rainer
