Approaches for targeting the mycobactin biosynthesis pathway for novel anti-tubercular drug discovery: where we stand

ABSTRACT

Introduction

Several decades of antitubercular drug discovery efforts have focused on novel antitubercular chemotherapies. However, recent efforts have greatly shifted toward countering extremely/multi/total drug-resistant species. Targeting the conditionally essential elements inside Mycobacterium is a relatively new approach against tuberculosis and has received lackluster attention. The siderophore, Mycobactin, is a conditionally essential molecule expressed by mycobacteria in iron-stress conditions. It helps capture the micronutrient iron, essential for the smooth functioning of cellular processes.

Areas covered

The authors discuss opportunities to target the conditionally essential pathways to help develop newer drugs and prolong the shelf life of existing therapeutics, emphasizing the bottlenecks in fast-tracking antitubercular drug discovery.

Expert opinion

While the lack of iron supply can cripple bacterial growth and multiplication, excess iron can cause oxidative overload. Constant up-regulation can strain the bacterial synthetic machinery, further slowing its growth. Mycobactin synthesis is tightly controlled by a genetically conserved mega enzyme family via up-regulation (HupB) or down-regulation (IdeR) based on iron availability in its microenvironment. Furthermore, the recycling of siderophores by the MmpL-MmpS4/5 orchestra provides endogenous drug targets to beat the bugs with iron-toxicity contrivance. These processes can be exploited as chinks in the armor of Mycobacterium and be used for new drug development.

KEYWORDS:

• Drug resistance
• essential targets
• conditionally essential targets
• iron-starvation
• iron-toxicity
• HupB
• IdeR
• MbtA
• MbtI
• efflux-pump

Article highlights

• Non-nucleoside MbtA inhibitors are the best alternative to tackle an inferior PK profile of nucleoside MbtA analogs. We recommend pursuing the development of non-nucleoside MbtA inhibitors in the future.

• Crystallographic structures of HupB have been made available (PDB ID: 4DKY, 4PT4) in the literature in the past few years. These should be considered for high throughput screening (HTS) campaigns for drug discovery, scaffold hopping, and hit identification.

• Disrupting the magnesium metallostasis of mycobacteria can be an attractive strategy against MbtI. This can be accomplished by: 1) disruption of the Mg2+ transporter CorA protein, and 2) the development of a divalent ion chelator (considering the divalent nature of the Mg2+ ion). The HIV integrase strand transfer inhibitors Diketo Acid candidates (DKAs), i.e. L-731988, S-1360, S-CITEP, L-870810, could be repurposed to develop a divalent metal chelator.

• The single crystallographic structure available in PDB, 5KEI, is devoid of a co-crystallized ligand. An X-ray crystal structure of MbtA co-crystallized with a ligand binding its active site pocket should be considered to open doors to in silico drug development.

• We have discussed the key role of MbtH in solubilizing MbtB, MbtE, and MbtF in the above discussions. Considering its criticality as a chaperone protein, it should be considered a prime candidate for developing potential inhibitors. The X-ray crystal structure of this enzyme is available in the PDB (ID: 2N6G).

• To further explore the siderophore-drug conjugates with ‘trojan horse’ approach, studies can be performed by conjugating Mycobactin M, N, and S with 1st line TB drugs (isoniazid and rifampicin), which are on the verge of acquiring complete drug resistance.

• Using homology modeling or artificial intelligence-based tools such as AlphaFold2 to predict unexplored protein structures of NRPS-PKS members and implementing machine learning approaches for HIT identification might possibly accelerate the search for novel targets and newer antibiotics.

List of abbreviations

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Declaration of interest

M Shyam is supported by a Newton Bhabha PhD Placement Award (2019–2020) Jointly funded by Department of Biotechnology, Government of India and British Council, UK (BT/IN/NBPP/MS/20/2019-20 dt. 04/03/2020) as well as a Japan-Asia Youth Exchange Program Award (2019) and Sakura Science Exchange Program Award (2019) both funded by the Japan Science and Technology, Japan. M Shyam has also been awarded with a Senior Research Fellowship (2019–2020) and a Junior Research Fellowship (2017–2019) from the Science & Engineering Research Board (SERB) of the Department of Science and Technology (EMR/2016/000675), the Government of India. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Funding

This manuscript was not funded.