doi: 10.1016/bs.armc.2023.09.005.
Epub 2023 Oct 11.
The challenges and opportunities of developing small molecule inhibitors of MraY
Affiliations
- PMID: 39015353
- PMCID: PMC11250723
- DOI: 10.1016/bs.armc.2023.09.005
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The challenges and opportunities of developing small molecule inhibitors of MraY
Annu Rep Med Chem.
2023.
No abstract available
Figures
MraY enzyme catalyzes the transfer of phospho-MurNAc-pentapeptide (called Park’s nucleotide) from UDP-MurNAc-pentapeptide (UM5A) to undecaprenylphosphate (lipid carrier, C55-P) in the presence of Mg2+ as co-factor to produce peptidoglycan precursor, undecaprenyl-pyrophosphoryl-MurNAc-pentapeptide, also called Lipid I. Figure recreated with permission from Pandey P.; Chatterjee, S.; Berida, T.; et al. Identification of Potential Non-Nucleoside MraY Inhibitors for Tuberculosis Chemotherapy Using Structure-Based Virtual Screening. J. Biomol. Struct. Dyn. 2022, 40 (11), 4832–4849. https://doi.org/10.1080/07391102.2020.1862705 .
Sequence alignments of MraY of different lengths across different bacterial species: Aquifex aeolicus strain VF5 (O66465), 359 amino acids; Escherichia coli strain K12 (P0A6W3), 360 amino acids; Staphylococcus aureus strain NCTC 8325/PS 47 (Q2FZ93), 321 amino acids; Borrelia garinii subsp. bavariensis strain ATCC BAA-2496/DSM 23469/PBi (Q661W1), 351 amino acids; Mycobacterium tuberculosis strain ATCC 25618/H37Rv (P9WMW7), 359 amino acid, respectively. The amino acid residues across Gram-negative bacteria (AQUAE, ECOLI, BORGP), Gram-positive (STAA8), and mycobacteria (MYCTU) in dark blue are fully conserved. The less the amino acid residues are conserved, the lighter the blue highlight. The red stars indicate the amino acid residues in the active site of the MraY-bound inhibitors (nucleoside natural products) with reference to MraY Aquifex aeolicus (MraYAA). Uniprot and Clustal W in Jalview are used for sequence alignment.
Overview of the active site hotspots for MraY inhibition. Top: Surface representation of MraYAA with inhibitor binding site hot spots (HSs) color-coded with the barcode tool (below) as follows: uridine (hot pink), uridine-adjacent (HS1; lime), TM9b/LoopE (HS2; magenta), caprolactam (HS3; pink), hydrophobic (HS4; marine), Mg2+ (HS5; orange), and tunicamycin/sphaerimicin (HS6; deep olive). Bottom: The barcode tool presents a summary of nucleoside inhibitor interactions with different amino acid residues within the uridine pocket and the hotspots (HS) 1–6 in the MraY protein. Each labeled HS residue (MraYAA numbering) represents a distinct site within MraY. Each row pertains to a different compound: carbacaprazamycin (CAR), capuramycin (CAP), 3′-hydroxymureidomycin A (MUR), muraymycin D2 (MD2), tunicamycin (TUN), and sphaerimicin 1 (SPM-1). Dark gray squares indicate the formation of interactions between the inhibitor and residue, while white squares denote the absence of contact. Light gray squares suggest potential interactions where either the amino acid residue side chain or the inhibitor substructure lacks clarity in the crystal structure but likely participates in the binding interaction. Figure recreated from Mashalidis, E. H.; Kaeser, B.; Terasawa, Y.; Katsuyama, A.; Kwon, D.-Y.; Lee, K.; Hong, J.; Ichikawa, S.; Lee, S.-Y. Chemical Logic of MraY Inhibition by Antibacterial Nucleoside Natural Products. Nat. Commun. 2019, 10 (1), 2917. doi: https://doi.org/10.1038/s41467-019-10957-9 .
Non-nucleoside small inhibitors of MraY.
Non-nucleoside inhibitors of MraY derived from nucleoside natural product inhibitors.
Example of a non-nucleoside inhibitor of MraY, TunR3, derived from tunicamycin natural product.
MraY inhibitor, LSP-10-B06, from a structure-based virtual screening protocol.
Structures of top five ranking hits identified from e-pharmacophore screening and molecular-docking of MraYMtb homology model (From, Guruprasad, J. Biomol. Struct. Dyn. 2018).
Structures of three top-ranking hits and one lower-ranking in silico hits identified as MraYMtb inhibitors from a structure-based virtual screening.
Figure recreated with permission from Pandey P.; Chatterjee, S.; Berida, T.; et al. Identification of Potential Non-Nucleoside MraY Inhibitors for Tuberculosis Chemotherapy Using Structure-Based Virtual Screening. J. Biomol. Struct. Dyn. 2022, 40 (11), 4832–4849. https://doi.org/10.1080/07391102.2020.1862705 .
Lipopeptide-based non-nucleoside inhibitor of MraY, Amphomycin.
An example of α-helix peptidomimetics that is potent against E. coli.