Abstract
We have recently found that selected thio-disaccharides possess bactericidal effects against Mycobacterium tuberculosis but not against Escherichia coli or Staphylococcus aureus. Here, we selected spontaneous mutants displaying resistance against the investigated thio-glycoside. According to next-generation sequencing, four of six analyzed mutants which were resistant to high concentrations of the tested chemical carried nonsynonymous mutations in the gene encoding the PPE51 protein. The complementation of these mutants with an intact ppe51 gene returned their sensitivity to the wild-type level. The uptake of tritiated thio-glycoside was significantly more abundant in wild-type Mycobacterium tuberculosis compared to the strain carrying the mutated ppe51 gene. The ppe51 mutations or CRISPR-Cas9-mediated downregulation of PPE51 expression affected the growth of mutant strains on minimal media supplemented with disaccharides (maltose or lactose) but not with glycerol or glucose as the sole carbon and energy source. Taking the above into account, we postulate that PPE51 participates in the uptake of disaccharides by tubercle bacilli.
Highlights
Tuberculosis, caused by Mycobacterium tuberculosis (Mtb), is among the most serious bacterial infectious diseases of the modern world
Taking the above into account, we found that the depletion or mutation of PPE51 in Mtb affects the ability of tubercle bacilli to use disaccharides as a carbon source
It was recently reported that Mtb is sensitive to thio-functionalized carbohydrate derivatives, including thio-glycoside, thio-semicarbazone, aminothiazole and thiazoline [39]
Summary
Tuberculosis, caused by Mycobacterium tuberculosis (Mtb), is among the most serious bacterial infectious diseases of the modern world. The World Health Organization [1] estimates that, each year, approximately ten million people fall ill with the disease and 1.5 million people die. Tuberculosis therapy lasts 6 to 24 months, depending on the drug susceptibility of the infecting bacterial strain and its metabolic state. The treatment of multi-drug-resistant tuberculosis (MDR-TB) is very expensive, very difficult for patients to follow, carries a burden of side effects and is successful only in about 54% [2,3]. As determined by the sequencing of the first Mtb genome, 7% of its total. The C-termini of PE and PPE remain highly variable [5]
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