An Overview on the Potential Antimycobacterial Agents Targeting Serine/Threonine Protein Kinases from Mycobacterium tuberculosis

Mori, Matteo; Sammartino, José Camilla; Costantino, Luca; Gelain, Arianna; Meneghetti, Fiorella; Villa, Stefania; Chiarelli, Laurent R.

doi:10.2174/1568026619666190227182701

Cited by 24 publications

(26 citation statements)

References 139 publications

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“…Therefore, there is an urgent need to identify novel druggable targets for the development of more efficient anti-TB agents [2,3]. In this context, the medicinal chemistry efforts made in the last years led to the discovery of new antimycobacterial compounds, and the identification of novel targets [3][4][5].…”

Section: The Added Value Of Promiscuous Targets For Antitubercular Drmentioning

confidence: 99%

Promiscuous Targets for Antitubercular Drug Discovery: The Paradigm of DprE1 and MmpL3

et al. 2020

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The development and spread of Mycobacterium tuberculosis multi-drug resistant strains still represent a great global health threat, leading to an urgent need for novel anti-tuberculosis drugs. Indeed, in the last years, several efforts have been made in this direction, through a number of high-throughput screenings campaigns, which allowed for the identification of numerous hit compounds and novel targets. Interestingly, several independent screening assays identified the same proteins as the target of different compounds, and for this reason, they were named “promiscuous” targets. These proteins include DprE1, MmpL3, QcrB and Psk13, and are involved in the key pathway for M. tuberculosis survival, thus they should represent an Achilles’ heel which could be exploited for the development of novel effective drugs. Indeed, among the last molecules which entered clinical trials, four inhibit a promiscuous target. Within this review, the two most promising promiscuous targets, the oxidoreductase DprE1 involved in arabinogalactan synthesis and the mycolic acid transporter MmpL3 are discussed, along with the latest advancements in the development of novel inhibitors with anti-tubercular activity.

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Section: The Added Value Of Promiscuous Targets For Antitubercular Drmentioning

confidence: 99%

Promiscuous Targets for Antitubercular Drug Discovery: The Paradigm of DprE1 and MmpL3

et al. 2020

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“…Additionally, it is required for the formation of mycobacterial biofilms and is involved in the development of anti-TB drug resistance in mycobacteria. Targeting Mt PknG represents one possible approach for the discovery of new anti-TB drugs [9,10,11,12,13,14,15,16,17,18,19,20,21,22,23].…”

Section: Introductionmentioning

confidence: 99%

Predictive Binding Affinity of Plant-Derived Natural Products Towards the Protein Kinase G Enzyme of Mycobacterium tuberculosis (MtPknG)

Qasaymeh

Rotondo

Oosthuizen

et al. 2019

Plants

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Tuberculosis (TB), caused by Mycobacterium tuberculosis, is a growing public health concern worldwide, especially with the emerging challenge of drug resistance to the current drugs. Efforts to discover and develop novel, more effective, and safer anti-TB drugs are urgently needed. Products from natural sources, such as medicinal plants, have played an important role in traditional medicine and continue to provide some inspiring templates for the design of new drugs. Protein kinase G, produced by M. tuberculosis (MtPKnG), is a serine/threonine kinase, that has been reported to prevent phagosome-lysosome fusion and help prolong M. tuberculosis survival within the host’s macrophages. Here, we used an in silico, target-based approach (docking) to predict the interactions between MtPknG and 84 chemical constituents from two medicinal plants (Pelargonium reniforme and Pelargonium sidoides) that have a well-documented historical use as natural remedies for TB. Docking scores for ligands towards the target protein were calculated using AutoDock Vina as the predicted binding free energies. Ten flavonoids present in the aerial parts of P. reniforme and/or P. sidoides showed docking scores ranging from −11.1 to −13.2 kcal/mol. Upon calculation of all ligand efficiency indices, we observed that the (−ΔG/MW) ligand efficiency index for flavonoids (4), (5) and (7) was similar to the one obtained for the AX20017 control. When taking all compounds into account, we observed that the best (−ΔG/MW) efficiency index was obtained for coumaric acid, coumaraldehyde, p-hydroxyphenyl acetic acid and p-hydroxybenzyl alcohol. We found that methyl gallate and myricetin had ligand efficiency indices superior and equal to the AX20017 control efficiency, respectively. It remains to be seen if any of the compounds screened in this study exert an effect in M. tuberculosis-infected macrophages.

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“…Some of these genes are known targets for antimycobacterial and/or antimicrobial agents. PknB, the ser/thr protein kinase critical for PG biosynthesis (Chawla et al, 2014;Turapov et al, 2018), has been explored as a target for antimycobacterial agents (Mori et al, 2019), for example. MurI (locus IV) is a glutamate racemase essential for PG biosynthesis in both M. tuberculosis and M. smegmatis (Li et al, 2014;Morayya et al, 2015) and it is a known target of anti-TB chemotherapeutics (Prosser et al, 2016;Pawar et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

Construction and Use of Transposon MycoTetOP2 for Isolation of Conditional Mycobacteria Mutants

2020

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Mycobacteria are unique in many aspects of their biology. The development of genetic tools to identify genes critical for their growth by forward genetic analysis holds great promises to advance our understanding of their cellular, physiological and biochemical processes. Here we report the development of a novel transposon, MycoTetOP 2 , to aid the identification of such genes by direct transposon mutagenesis. This mariner-based transposon contains nested anhydrotetracycline (ATc)-inducible promoters to drive transcription outward from both of its ends. In addition, it includes the Escherichia coli R6Kγ origin to facilitate the identification of insertion sites. MycoTetOP 2 was placed in a shuttle plasmid with a temperature-sensitive DNA replication origin in mycobacteria. This allows propagation of mycobacteria harboring the plasmid at a permissive temperature. The resulting population of cells can then be subjected to a temperature shift to select for transposon mutants. This transposon and its delivery system, once constructed, were tested in the fast-growing model Mycobacterium smegmatis and 13 mutants with ATc-dependent growth were isolated. The identification of the insertion sites in these mutants led to nine unique genetic loci with genes critical for essential processes in both M. smegmatis and Mycobacterium tuberculosis. These results demonstrate that MycoTetOP 2 and its delivery vector provide valuable tools for the studies of mycobacteria by forward genetics.

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An Overview on the Potential Antimycobacterial Agents Targeting Serine/Threonine Protein Kinases from Mycobacterium tuberculosis

Cited by 24 publications

References 139 publications

Promiscuous Targets for Antitubercular Drug Discovery: The Paradigm of DprE1 and MmpL3

Promiscuous Targets for Antitubercular Drug Discovery: The Paradigm of DprE1 and MmpL3

Predictive Binding Affinity of Plant-Derived Natural Products Towards the Protein Kinase G Enzyme of Mycobacterium tuberculosis (MtPknG)

Construction and Use of Transposon MycoTetOP2 for Isolation of Conditional Mycobacteria Mutants

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