Abstract
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.
Highlights
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
The importance of these promiscuous targets can be exemplified by the numerous papers that report novel compound(s) able to exert antimycobacterial activity targeting these proteins, but the presence of drug candidates in the antitubercular pipeline better highlight the relevance of promiscuous targets
Is at the interface of the substrate-binding domain and the cofactor-binding domain, where are located in located at the interface of the substrate-binding domain and the cofactor-binding domain, where are located in two disordered loops, which have been supposed to be involved in interactions with the DPR substrate, or with other proteins involved in the decaprenylphosphoryl arabinose (DPA) biosynthesis [42]
Summary
One of the biggest problems in fighting Mycobacterium tuberculosis (Mtb), the etiologic agent of tuberculosis (TB), is the development and spread of multi-drug resistant strains [1]. An unforeseen outcome of many phenotypic screens against Mtb is the finding that the same targets have been frequently found in many different screening assays, despite the use of different compound libraries [11] These targets were named “promiscuous” targets, for their nonspecific susceptibility to being inhibited by different scaffolds [2,12]. It is noteworthy that several research groups independently identified these promiscuous targets These proteins are embedded in pathways that have key roles for Mtb growth and survival under the screening conditions, but even more important during infection. Their essentiality represents an Mtb. Achilles’ heel that is important to exploit for the development of new effective drug regimens able to shorten the TB treatment. In parallel, a rational exploitation of already available promiscuous targets could lead to optimized scaffolds that retain the ability to attack the most vulnerable weakness of tubercle bacilli
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