Reaching toward underexplored targets in antibacterial drug design

Abstract

The increase of antimicrobial resistance necessitates the renewal and strong research involvement in antibacterial drug design. In the following work, we comment on the key approaches used in development of new antibacterials, focusing on intracellular therapeutic targets that have been so far mostly underexplored: the enzymes of the Mur pathway MurA to MurF. We identify common obstacles observed during research on MurA, MurB, and Mur ligases inhibitors and their development into potential antibacterial compounds, and discern several approaches and solutions to tackle the whole‐cell activity of designed compounds. Furthermore, we consolidate recent literature reports and encourage the further research on Mur enzymes.

Toward a structome of Acinetobacter baumannii drug targets

“…MurF catalyzes the last step of the cytoplasmic phase of peptidoglycan biosynthesis which is crucial to bacterial cell wall synthesis . This is an ATP‐dependent reaction utilizing d ‐ala‐ d ‐ala and UDP‐ N ‐acetyl‐muramoyl‐Ala‐ d ‐Glu‐ l ‐Lys to form UDP‐ N ‐acetyl‐ d ‐muramoyl‐ l ‐Ala‐ d ‐Glu‐ l ‐Lys‐ d ‐Ala‐ d ‐Ala (UDP‐ N ‐acetylmuramate‐pentapeptide) . Only one inhibitor, fosfomycin, has been clinically used as an effective antibiotic MurA inhibitor.…”

“…UDP‐ N ‐acetylmuramate—alanine ligase (MurC) facilitates the first ATP‐dependent peptide addition to UDP‐ N ‐acetylmuramate starting the peptide chain of UDP‐ N ‐acetylmuramate‐pentapeptide . Similar to MurF, several inhibitors of the MurC have been reported; however, little show effective antibacterial activity aside from inhibitors with an N ‐acylhydrazone scaffold that had dual inhibitory activity with MurC and MurD …”

“…53 This is an ATP-dependent reaction utilizing D-ala-D-ala and UDP-N-acetyl-muramoyl-Ala-D-Glu-L-Lys to form UDP-N-acetyl-D-muramoyl-L-Ala-D-Glu-L-Lys-D-Ala-D-Ala (UDP-N-acetylmuramate-pentapeptide). 52,54 Only one inhibitor, fosfomycin, has been clinically used as an effective antibiotic MurA inhibitor. While there have been many reported inhibitors of MurF, many do not show antibacterial activity even with cell permeabilizers.…”

“…55,56 UDP-N-acetylmuramate-alanine ligase (MurC) facilitates the first ATP-dependent peptide addition to UDP-N-acetylmuramate starting the peptide chain of UDP-N-acetylmuramate-pentapeptide. 54 Similar to MurF, several inhibitors of the MurC have been reported; however, little show effective antibacterial activity aside from inhibitors with an N-acylhydrazone scaffold that had dual inhibitory activity with MurC and MurD. 55,57 2-Dehydro-3-deoxyphosphooctonate aldolase catalyzes the formation of 3-deoxy-D-manno-octulosonate 8-phosphate (Kdo8P) from phosphoenolpyruvate (PEP) and D-arabinose-5-phosphate.…”

Bioinformatic Exploration of Metal-Binding Proteome of Zoonotic Pathogen Orientia tsutsugamushi

“…Previously, an in silico study stated that metabolic pathway proteins of Ott may act as probable target for drug discovery process (Sharma et al, 2018b). It is a well-established fact that Mur enzymes are involved in biosynthesis of bacterial cell wall using divalent metal ions as cofactor and are best intracellular therapeutic targets (Munshi et al, 2013; Moraes et al, 2015; Jukič et al, 2019). DDI enzyme uses Mg 2+ ion as cofactor and catalyzes early steps of peptidoglycan synthesis, i.e., formation of D-Ala-D-Ala and D-Ala-D-Ser dipeptides in bacteria (Tytgat et al, 2009).…”