Molecular Docking Studies of Some Designed Siderophore-conjugated Meropenem Derivatives for Combating Multidrug Resistant-TB

Abstract

Aim: The rise of multidrug-resistant tuberculosis (MDR-TB) presents a significant challenge to existing treatment approaches, highlighting the urgent need for innovative therapeutic strategies. This research focused on designing siderophore-conjugated meropenem derivatives to target the iron acquisition pathways of M. tuberculosis and tested using docking techniques (IrtAB, PDB ID: 7WIV). Methods: A hydroxamate group was attached to meropenem using various linkers, including disulfide, quaternary ammonium, alkyl, and triazole, to facilitate Fe³⁺ chelation. The docking studies were performed using PyRx software and visualized in Chimera and Biovia Discovery Studio. Initially, meropenem alone was docked to evaluate its interaction with the receptor IrtAB, followed by docking studies with beta-lactamase to assess the compound's resistance to enzymatic degradation, and finally with serine/threonine-protein kinase (PDB ID: 4OW8) to evaluate its antibacterial potential. Later, the derivatives with siderophore were docked against the IrtAB receptor for evaluating permeability. Results: Meropenem exhibited favorable results in all cases except binding with IrtAB which is due to its hydrophilic nature. Subsequently, docking studies on siderophore-conjugated meropenem derivatives indicated high binding affinities. These affinities increased further upon Fe³⁺ attachment. Compounds with quaternary ammonium group and triazole group as linkers show the best interaction (SW-4A and SW-10A). After the hydroxamate group chelates ferric ions in the body, the IrtAB receptor facilitates the transport of the siderophore-conjugated meropenem-ferric complex through the mycolic acid layer. Conclusion: This study provides valuable insights into the potential of siderophore-conjugated meropenem derivatives as a novel therapeutic approach for multidrug-resistant tuberculosis. This mechanism potentially overcomes the less-permeability of meropenem caused by its hydrophilic nature and, with the help of its resistance to beta-lactamase enzyme, presents a promising avenue for MDR-TB treatment. Furthermore, the meropenem demonstrated resistance against beta-lactamase and proved antibacterial activity by interacting with PknA, a key regulatory protein.