New Noncovalent Inhibitors of Penicillin-Binding Proteins from Penicillin-Resistant Bacteria

Abstract

BackgroundPenicillin-binding proteins (PBPs) are well known and validated targets for antibacterial therapy. The most important clinically used inhibitors of PBPs β-lactams inhibit transpeptidase activity of PBPs by forming a covalent penicilloyl-enzyme complex that blocks the normal transpeptidation reaction; this finally results in bacterial death. In some resistant bacteria the resistance is acquired by active-site distortion of PBPs, which lowers their acylation efficiency for β-lactams. To address this problem we focused our attention to discovery of novel noncovalent inhibitors of PBPs.Methodology/Principal FindingsOur in-house bank of compounds was screened for inhibition of three PBPs from resistant bacteria: PBP2a from Methicillin-resistant Staphylococcus aureus (MRSA), PBP2x from Streptococcus pneumoniae strain 5204, and PBP5fm from Enterococcus faecium strain D63r. Initial hit inhibitor obtained by screening was then used as a starting point for computational similarity searching for structurally related compounds and several new noncovalent inhibitors were discovered. Two compounds had promising inhibitory activities of both PBP2a and PBP2x 5204, and good in-vitro antibacterial activities against a panel of Gram-positive bacterial strains.ConclusionsWe found new noncovalent inhibitors of PBPs which represent important starting points for development of more potent inhibitors of PBPs that can target penicillin-resistant bacteria.

Synergistic antibacterial effects of herbal extracts and antibiotics on methicillin-resistant Staphylococcus aureus: A computational and experimental study

“…Docking was performed on the X-ray crystallography structure of PBP2a (PDB: 4CJN) and the 11,421 ligands from the Zinc In Man database, 42 plus eight experimentally approved PBP2a inhibitors with IC 50 less than 100 mM. 43 These eight approved inhibitors served as the ''true'' hits in this validation. Added together, a ligand library of 11,429 was formed.…”

Inhibition of WTA Synthesis Blocks the Cooperative Action of PBPs and Sensitizes MRSA to β-Lactams

“…10,11 Others strategies to treat MRSA have centered on the development of new drug classes with orthogonal mechanisms to the β-lactams such as linezolid, daptomycin, and new glycopeptides. 12 Nevertheless resistance to these novel classes has already been reported.…”

Viable screening targets related to the bacterial cell wall

“…A number of non‐β‐lactam compounds have been reported that bind to and, in some cases, inhibit certain PBPs. These include derivatives of rhodanines, 119 boronates, 120–122 several dyes, 123 4‐quinolones, 124 and some substituted benzoic acids 34 . Of these, only the boronates are thought to be covalent, albeit reversible, inhibitors.…”

“…These include derivatives of rhodanines, 119 boronates, 120-122 several dyes, 123 4-quinolones, 124 and some substituted benzoic acids. 34 Of these, only the boronates are thought to be covalent, albeit reversible, inhibitors. Any antibacterial activity associated with these non-␤lactam compounds has not been causally linked to PBP binding.…”