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Benzoylphenyl thiocyanates are new, effective inhibitors of the mycobacterial resuscitation promoting factor B protein.

ABSTRACT: Resuscitation promoting factors (Rpfs) are the proteins involved in the process of reactivation of the dormant cells of mycobacteria. Recently a new class of nitrophenylthiocyanates (NPTs), capable of inhibiting the biological and enzymatic activities of Rpfs has been discovered. In the current study the inhibitory properties of the compounds containing both nitro and thiocyanate groups alongside with the compounds with the modified number and different spatial location of the substituents are compared.New benzoylphenyl thiocyanates alongside with nitrophenylthiocyanates were tested in the enzymatic assay of bacterial peptidoglycan hydrolysis as well as against strains of several actinobacteria (Mycobacterium smegmatis, Mycobacterium tuberculosis) on in-lab developed models of resuscitation of the dormant forms.Introduction of the additional nitro and thiocyanate groups to the benzophenone scaffold did not influence the inhibitory activity of the compounds. Removal of the nitro groups analogously did not impair the functional properties of the molecules. Among the tested compounds two molecules without nitro group: 3-benzoylphenyl thiocyanate and 4-benzoylphenyl thiocyanate demonstrated the maximum activity in both enzymatic assay (inhibition of the Rpf-mediated peptidoglycan hydrolysis) and in the resuscitation assay of the dormant M. tuberculosis cells.The current study demonstrates dispensability of the nitro group in the NPT's structure for inhibition of the enzymatic and biological activities of the Rpf protein molecules. These findings provide new prospects in anti-TB drug discovery especially in finding of molecular scaffolds effective for the latent infection treatment.

SUBMITTER: Demina GR

PROVIDER: S-EPMC5667462 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Benzoylphenyl thiocyanates are new, effective inhibitors of the mycobacterial resuscitation promoting factor B protein.

Demina Galina R GR Nikitushkin Vadim D VD Shleeva Margarita O MO Riabova Olga B OB Lepioshkin Alexander Yu AY Makarov Vadim A VA Kaprelyants Arseny S AS

Annals of clinical microbiology and antimicrobials 20171102 1

<h4>Background</h4>Resuscitation promoting factors (Rpfs) are the proteins involved in the process of reactivation of the dormant cells of mycobacteria. Recently a new class of nitrophenylthiocyanates (NPTs), capable of inhibiting the biological and enzymatic activities of Rpfs has been discovered. In the current study the inhibitory properties of the compounds containing both nitro and thiocyanate groups alongside with the compounds with the modified number and different spatial location of the ...[more]

PMID: 29096645

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Project description:Sirtuin 1 (Sirt1) is a NAD+ dependent lysine deacetylase associated with the pathogenesis of various diseases including cancer. In many cancer types Sirt1 expression is increased and higher levels have been associated with metastasis and poor prognosis. However, it was also shown, that Sirt1 can have tumor suppressing properties and in some instances even a dual role for the same cancer type has been reported. Increased Sirt1 activity has been linked to extension of the life span of cells, respectively, organisms by promoting DNA repair processes and downregulation of tumor suppressor proteins. This may have the downside of enhancing tumor growth and metastasis. In mice embryonic fibroblasts depletion of Sirt1 was shown to decrease levels of the DNA damage sensor histone H2AX. Impairment of DNA repair mechanisms by Sirt1 can promote tumorigenesis but also lower chemoresistance toward DNA targeting therapies. Despite many biological studies, there is currently just one small molecule Sirt1 inhibitor in clinical trials. Selisistat (EX-527) reached phase III clinical trials for treatment of Huntington's Disease. New small molecule Sirt1 modulators are crucial for further investigation of the contradicting roles of Sirt1 in cancer. We tested a small library of commercially available compounds that were proposed by virtual screening and docking studies against Sirt1, 2 and 3. A thienopyrimidone featuring a phenyl thiocyanate moiety was found to selectively inhibit Sirt1 with an IC50 of 13 ?M. Structural analogs lacking the thiocyanate function did not show inhibition of Sirt1 revealing this group as key for the selectivity and affinity toward Sirt1. Further analogs with higher solubility were identified through iterative docking studies and in vitro testing. The most active compounds (down to 5 ?M IC50) were further studied in cells. The ratio of phosphorylated ?H2AX to unmodified H2AX is lower when Sirt1 is depleted or inhibited. Our new Sirtuin 1 inhibiting thiocyanates (S1th) lead to similarly lowered ?H2AX/H2AX ratios in mouse embryonic fibroblasts as Sirt1 knockout and treatment with the reference inhibitor EX-527. In addition to that we were able to show antiproliferative activity, inhibition of migration and colony forming as well as hyperacetylation of Sirt1 targets p53 and H3 by the S1th in cervical cancer cells (HeLa). These results reveal thiocyanates as a promising new class of selective Sirt1 inhibitors.

Project description:The anaerobic bioremediation of polychlorinated biphenyls (PCBs) is largely impeded by difficulties in massively enriching PCB dechlorinators in short periods of time. Tetrachloroethene (PCE) is often utilized as an alternative electron acceptor to preenrich PCB-dechlorinating bacteria. In this study, resuscitation promoting factor (Rpf) was used as an additive to enhance the enrichment of the microbial communities involved in PCE/PCBs dechlorination. The results indicated that Rpf accelerates PCE dechlorination 3.8 to 5.4 times faster than control cultures. In Aroclor 1260-fed cultures, the amendment of Rpf enables significantly more rapid and extensive dechlorination of PCBs. The residual high-chlorinated PCB congeners (≥5 Cl atoms) accounted for 36.7% and 59.8% in the Rpf-amended cultures and in the corresponding controls, respectively. This improvement was mainly attributed to the enhanced activity of the removal of meta-chlorines (47.7 mol % versus 14.7 mol %), which did not appear to affect dechlorination pathways. The dechlorinators, including Dehalococcoides in Chloroflexi and Desulfitobacterium in Firmicutes, were greatly enriched via Rpf amendment. The abundance of nondechlorinating populations, including Methanosarcina, Desulfovibrio, and Bacteroides, was also greatly enhanced via Rpf amendment. These results suggest that Rpf serves as an effective additive for the rapid enrichment of active dechlorinating cultures so as to provide a new approach by which to massively cultivate bioinoculants for accelerated in situ anaerobic bioremediation. IMPORTANCE The resuscitation promoting factor (Rpf) of Micrococcus luteus has been reported to resuscitate and stimulate the growth of functional microorganisms that are involved in the aerobic degradation of polychlorinated biphenyls (PCBs). However, few studies have been conducted to investigate the role of Rpf on anaerobic microbial populations. In this study, the enhancement of Rpf on the anaerobic microbial dechlorination of PCE/PCBs was discovered. Additionally, the Rpf-responsive populations underlying the enhanced dechlorination were uncovered. This report reveals the rapid enrichment of active dechlorinating cultures via Rpf amendment, and this sheds light on massively enriching PCB dechlorinators in short periods of time. The enhanced in situ anaerobic bioremediation of PCBs could be expected by supplementing Rpf.

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Benzoylphenyl thiocyanates are new, effective inhibitors of the mycobacterial resuscitation promoting factor B protein.

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Benzoylphenyl thiocyanates are new, effective inhibitors of the mycobacterial resuscitation promoting factor B protein.

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