In our previous study we have evaluated the bactericidal activity of thio-functionalized carbohydrate derivatives (1-3). A few of the investigated compounds presented a potent activity against tubercle bacilli (Mtb), the causative agent of tuberculosis. The compounds affecting the growth of mycobacteria were either thiodisaccharides or thioglycosides. All of these compounds were able to inhibit the growth of Mtb deposited within human macrophages. Here, we have selected spontaneous mutants displaying resistance against investigated thiosugars. The resistant-mutants selected in three independent experiments were subjected to the genome analysis using next generation sequencing (NGS, MiSeq Illumina). Five of six analyzed mutants, resistant to high concentrations of the tested chemicals, carried nonsynonymous mutations in the ppe51 gene (named after their N-terminal Pro-Pro-Glu (PPE) motifs). Next, the Mtb ppe51 mutants were transformed with plasmid DNA carrying a wild type copy of ppE51 resulting in the reversal of the resistant phenotype to the wild type level. The effect of PPE51 protein depletion, the uptake of thiosugars by wild type and ppe51 Mtb mutants, as well as, the interaction of PPE51 and the investigated compounds were also evaluated in this work.

PPE51-mutation effect the sensitivity of Tubercle bacilli to selected thio-sugars

2019 Spring National Meeting

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