Title:Shikimate Kinase Inhibitors: An Update on Promising Strategy against Mycobacterium tuberculosis
Volume: 24
Issue: 5
Author(s): Vikrant Singh Rajput*, Ashish Runthala and Inshad Ali Khan*
Affiliation:
- Department of Biomedical Engineering, Central University of Rajasthan, NH-8, Bandarsindri, Kishangarh, 305817, Ajmer, Rajasthan, India
- Department of Microbiology, Central University of Rajasthan, NH-8, Bandarsindri, Kishangarh, 305817, Ajmer, Rajasthan, India
Keywords:
M. tuberculosis, shikimate, pathway, shikimate kinase, inhibitors, MtSK inhibitors.
Abstract: Humanity has been battling with tuberculosis (TB) for a long period, and despite the
availability of drugs well-known to act against the deadly microbe, the menace is still very far from
reaching its end. Moreover, problems related to TB chemotherapy, such as lengthy treatment periods
leading to poor patient compliance, increasing drug resistance, and association with another
deadlier disease HIV-AIDS, make the situation alarming, thereby pressing the need for the discovery
of new potent drugs urgently. Therefore, a drug target that is essential for survival and exclusive
to M. tuberculosis presents a promising platform to explore novel molecules against the microorganism
for better pathogen clearance with minimal toxicity. The shikimate pathway that leads to the
synthesis of essential aromatic amino acids is one such attractive target. Shikimate kinase, the fifth
enzyme of this pathway, converts shikimate to shikimate-3-phosphate by using ATP as a cosubstrate.
Targeting shikimate kinase could be an effective strategy in light of its essentiality and
absence of any homologue in mammals. This review discusses different strategies adopted for discovering
novel compounds or scaffolds targeting M. tuberculosis shikimate kinase (MtSK) in vitro.
The application of substrate analogues, their structure, and ligand-based approach for screening a
library of anti-mycobacterial compounds, marine-derived molecules, and commercially available
libraries have yielded promising MtSK inhibitors exhibiting micro-molar activities. To develop
these leads into future drugs with minimum off-target effects on the host microenvironment, the
molecules need to be structurally optimized for improved activities against enzymes and whole-cell
organisms.
