Mycobacterium tuberculosis-Secreted Tyrosine Phosphatases as Targets Against Tuberculosis: Exploring Natural Sources in Searching for New Drugs

Abstract

Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis (Mtb), which primarily affects the respiratory tract. Combinations of drugs are used for therapeutic synergism and to prevent the emergence of drug resistant strains, but even first- or secondchoice drugs present some disadvantages, such as significant side effects and the need for long duration of treatments. Thus, new strategies for TB control and treatment are highly demanded. In this context, protein tyrosine phosphatases (PtpA and PtpB) are secreted by Mtb within the host macrophage and they have been shown to contribute to Mtb pathogenicity. The understanding of the role of these PTPs has led to interesting anti-TB drugs discovery. Here, we review the current knowledge on these two proteins as targets for novel anti-TB therapies, with particular emphasis on their mechanism of action and current advancements in developing small molecule inhibitors from natural sources.

The Role of the Phosphorus Atom in Drug Design

“…Other closely related phosphate analogues that have been used as interesting phosphorus‐containing compounds are those reported some years ago . Some aryl phosphates were the starting point for the development of relatively efficient inhibitors of Mycobacterium tuberculosis phosphatase PtpB . Starting from substrate identification from simple O ‐aryl phosphates such as 131 – 134 followed by substrate optimization (compounds 135 – 137 ), these compounds were converted into inhibitors by replacing the phosphate moiety with a pharmacophore that behaved as an inhibitor, giving rise to 138 , which exhibited effective inhibitory action toward M. tuberculosis phosphatase PtpB as shown in Scheme .…”

Pharmacological Properties of Morus nigra L. (Black Mulberry) as A Promising Nutraceutical Resource

“…TB is a curable and preventive disease, but resistance against conventional antibiotic medications for M. tuberculosis has increased the number of cases of multidrug-resistant or extensively drug-resistant TB [29]. In this respect, demand for new medications with novel therapeutic targets such as protein tyrosinase phosphatases (PTPs) is growing [30,31]. Mascarello et al [32] evaluated the anti-tuberculosis activity of Diel–Alder-type adducts from M. nigra root bark to determine their potential as candidates for M. tuberculosis PTP inhibitor.…”

A significant therapeutic effect of silymarin administered alone, or in combination with chemotherapy, in experimental pulmonary tuberculosis caused by drug-sensitive or drug-resistant strains: In vitro and in vivo studies

“…Thus, it is important to obtain shorter and less-toxic therapeutic regimens [51,52] that can also be used for preventive therapy [40]. Natural products are an attractive alternative in the search for new drugs with antibiotic [16, 53], antioxidant or hepatoprotective effects to treat the rapidly growing numbers of cases of MDR and XDR TB [54]. This is the case with a standardized extract from Sm, which is safe (low side-effect profile) and has been used as antioxidant and hepatoprotective agent for liver [55, 56].…”