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Therapeutic Targeting of Protein Tyrosine Phosphatases from Mycobacterium Tuberculosis

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Therapeutic Targeting of Protein Tyrosine Phosphatases from Mycobacterium Tuberculosis microorganisms Review Therapeutic Targeting of Protein Tyrosine Phosphatases from Mycobacterium tuberculosis Kasi Viswanatharaju Ruddraraju 1 , Devesh Aggarwal 1 and Zhong-Yin Zhang 1,2,3,* 1 Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN 47907, USA; [email protected] (K.V.R.); [email protected] (D.A.) 2 Department of Chemistry, Purdue University, West Lafayette, IN 47907, USA 3 Institute for Drug Discovery, Purdue University, West Lafayette, IN 47907, USA * Correspondence: [email protected] Abstract: Tuberculosis (TB) is an airborne infectious disease caused by Mycobacterium tuberculosis (Mtb). According to the World Health Organization, an estimated 10 million people developed TB in 2018. The occurrence of drug-resistant TB demands therapeutic agents with novel mechanisms of action. Antivirulence is an alternative strategy that targets bacterial virulence factors instead of central growth pathways to treat disease. Mycobacterium protein tyrosine phosphatases, mPTPA and mPTPB, are secreted by Mtb into the cytoplasm of macrophages and are required for survival and growth of infection within the host. Here we present recent advances in understanding the roles of mPTPA and mPTPB in the pathogenesis of TB. We also focus on potent, selective, and well-characterized small molecule inhibitors reported in the last decade for mPTPA and mPTPB. Keywords: protein tyrosine phosphatases (PTPs); tuberculosis (TB); Mycobacterium tuberculosis (Mtb); signal transduction; virulence factors; pathogenic microorganisms; PTP inhibitors; salicylic acid derivatives; oxamic acids 1. Introduction Citation: Ruddraraju, K.V.; Aggarwal, Tuberculosis (TB) is an airborne infectious disease caused by the intracellular pathogen D.; Zhang, Z. Therapeutic Targeting of Mycobacterium tuberculosis (Mtb). TB is one of the top 10 causes of human death worldwide Protein Tyrosine Phosphatases from My- cobacterium tuberculosis. Microorganisms and the leading cause of death from a single infectious agent. According to the World 2021, 9, 14. https://dx.doi.org/10.3390/ Health Organization (WHO, 2018 tuberculosis report), an estimated 10 million people microorganisms9010014 developed TB, and over 1.2 million people succumbed to it in 2018. It is also estimated that about a quarter of the global population has latent TB. Current TB treatment is based Received: 27 November 2020 on combination chemotherapy and requires 6 to 9 months of treatment. However, due to Accepted: 21 December 2020 increasing drug resistance, antibiotics are losing efficacy in treating TB. Inadequate diagno- Published: 23 December 2020 sis, lack of compliance from patients, irregular drug supply, poor bioavailability of drugs, and mutation/gene transfer are some of the factors contributing to drug resistance [1]. Ac- Publisher’s Note: MDPI stays neu- cording to the WHO, there are currently 50 antibiotics in the clinical pipeline [2]. However, tral with regard to jurisdictional claims this clinical pipeline is insufficient to tackle the problem of increasing antibiotic resistance. in published maps and institutional Since July 2017, eight new antibiotics have been approved, but many have limited clinical affiliations. benefits compared to the existing treatments. The occurrence of multidrug-resistant and extensively drug-resistant tuberculosis demands the development of therapeutic agents with novel mechanisms of action [3]. Since early interactions between Mtb and the host Copyright: © 2020 by the authors. Li- innate immune system play essential roles in the establishment of TB infection and disease censee MDPI, Basel, Switzerland. This development, alternative therapeutic approaches such as antivirulence strategies are gain- article is an open access article distributed ing interest among researchers in the development of more effective TB therapies and in under the terms and conditions of the combating antibiotic resistance. Creative Commons Attribution (CC BY) Protein tyrosine phosphatases (PTPs) remove the phosphoryl group(s) from substrate license (https://creativecommons.org/ proteins (Figure1). Together with protein tyrosine kinases, PTPs regulate numerous cellular licenses/by/4.0/). functions, such as cell growth, proliferation, differentiation, metabolism, and immune Microorganisms 2021, 9, 14. https://dx.doi.org/10.3390/microorganisms9010014 https://www.mdpi.com/journal/microorganisms MicroorganismsMicroorganisms 20202021,, 89,, x 14 FOR PEER REVIEW 22 of of 13 13 Microorganisms 2020, 8, x FOR PEER REVIEW 2 of 13 cellular functions, such as cell growth, proliferation, differentiation, metabolism, and im‐ mune response. Not surprisingly, abnormal regulation of PTPs can cause cancer, diabetes response.cellular functions, Not surprisingly, such as cell abnormal growth, regulation proliferation, of PTPs differentiation, can cause cancer, metabolism, diabetes and and im‐ and obesity, autoimmune disorders, and neurodegenerative diseases [4,5]. The im‐ obesity,mune response. autoimmune Not surprisingly, disorders, and abnormal neurodegenerative regulation of diseases PTPs can [4 cause,5]. The cancer, importance diabetes portance of PTPs in human diseases is further emphasized by the observations that they ofand PTPs obesity, in human autoimmune diseases is furtherdisorders, emphasized and neurodegenerative by the observations diseases that they[4,5]. are The often im‐ are often utilized by microbial organisms to avoid host immune clearance [4]. Bacterial utilizedportance by of microbial PTPs in organismshuman diseases to avoid is further host immune emphasized clearance by the [4]. observations Bacterial pathogens that they pathogens have developed diverse strategies to alter the host signaling processes to cir‐ haveare often developed utilized diverse by microbial strategies organisms to alter the to host avoid signaling host immune processes clearance to circumvent [4]. Bacterial the cumvent the hostile environment of the macrophages [6]. Studies have shown that Mtb hostilepathogens environment have developed of the macrophages diverse strategies [6]. Studies to alter have the host shown signaling that Mtb processes encodes to two cir‐ encodes two PTPs, Mycobacterium protein tyrosine phosphatase A (mPTPA; Rv2234) and PTPs,cumventMycobacterium the hostileprotein environment tyrosine of phosphatase the macrophages A (mPTPA; [6]. Studies Rv2234) have and shownMycobacterium that Mtb Mycobacterium protein tyrosine phosphatase B (mPTPB; Rv0153c), which are secreted by proteinencodes tyrosine two PTPs, phosphatase Mycobacterium B (mPTPB; protein Rv0153c), tyrosine whichphosphatase are secreted A (mPTPA; by the Rv2234) bacterium and the bacterium into the cytoplasm of host macrophages. These phosphatases directly alter intoMycobacterium the cytoplasm protein of host tyrosine macrophages. phosphatase These B phosphatases (mPTPB; Rv0153c), directly which alter hostare secreted signaling by host signaling to evade the antimicrobial functions of the host (Figure 2), thereby promot‐ tothe evade bacterium the antimicrobial into the cytoplasm functions of of host the hostmacrophages. (Figure2), therebyThese phosphatases promoting Mtb directly survival alter ing Mtb survival within the macrophages [7–9]. Consequently, mPTPA and mPTPB rep‐ withinhost signaling the macrophages to evade the [7– antimicrobial9]. Consequently, functions mPTPA of the and host mPTPB (Figure represent 2), thereby attractive promot‐ resent attractive targets for anti‐TB drug development. targetsing Mtb for survival anti-TB drugwithin development. the macrophages [7–9]. Consequently, mPTPA and mPTPB rep‐ resent attractive targets for antiSubstrate‐TB drug development. - Substrate -O O Substrate P O O HO H Arg17 (mPTPA) - Arg17 (mPTPA) Substrate Arg17 (mPTPA) -O O H2N N Arg166 (mPTPB) O O Arg166 (mPTPB) O O Arg166 (mPTPB) P HN H H HN HNO O Arg17 (mPTPA) - OH HO Arg17 (mPTPA) Asp126 (mPTPA) - HN H O O O H N N Arg166 (mPTPB) H HN Arg17 (mPTPA) O NH2 Arg166 (mPTPB) Asp82 (mPTPB) P 2 Asp126 (mPTPA) O HN O O NH2 Arg166 (mPTPB) H -O O Asp82 (mPTPB) O H HN HN HN H - OH HN Asp126 (mPTPA) - HN O - O O O O H O HN HN O NH2 Asp82 (mPTPB) NH - P Asp126 (mPTPA) - NH S O O NH2 - - O O PO S O H OH HN Asp82 (mPTPB)NH H H N N H S - O HN O O O N N O NH H - H HN O S- N O N NH - O O PO O S O H H NH H O H N N O S O N N Cys11 (mPTPA) H O H Cys11 (mPTPA) O PhosphocysteineN N O Cys160 (mPTPB) O Cys160 (mPTPB)O intermediateO Cys11 (mPTPA) O Cys11 (mPTPA) Cys160 (mPTPB) Phosphocysteine Cys160 (mPTPB) FigureFigure 1. 1. TheThe dephosphorylation dephosphorylation mechanism mechanism of ofprotein protein tyrosine tyrosineintermediate phosphatases phosphatases with with mPTPA mPTPA and andmPTPB mPTPB as examples. as examples. The residues are labeled in blue for mPTPA and in green for mPTPB. The dianionic phosphotyrosine (pTyr) binds to the posi‐ TheFigure residues 1. The are dephosphorylation labeled in blue for mechanism mPTPA and of in protein green tyrosine for mPTPB. phosphatases The dianionic with phosphotyrosine mPTPA and mPTPB (pTyr) as examples. binds to the The tively charged active site of PTPs. The active site cysteine thiol (Cys11 in mPTPA, Cys160 in mPTPB) possesses a pKa of positivelyresidues chargedare labeled active in blue site offor PTPs. mPTPA The and active in green site cysteine for mPTPB. thiol The (Cys11 dianionic in mPTPA, phosphotyrosine Cys160 in mPTPB) (pTyr) possessesbinds to the a pKa posi‐ ~5 and is predominantly in the thiolate form at neutral pH. When binding to pTyr substrates,
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