Aspergillomarasmine A inhibits metallo-β-lactamases by selectively sequestering Zn2+

Microbial Biotechnolog

Mechanistic investigations of metallo-β-lactamase inhibitors: strong zinc binding is not required for potent enzyme inhibition

Microbial Biotechnolog

Cephalosporin prodrug inhibitors overcome metallo-β-lactamase driven antibiotic resistance

Microbial Biotechnolog

Novel Cephalosporin conjugates display potent and selective inhibition of Imipenemase-type Metallo-β-Lactamases

Medicinal Chemistr

β-lactam/β-lactamase inhibitor combinations: an update

Antibiotic resistance caused by β-lactamase production continues to present a growing challenge to the efficacy of β-lactams and their role as the most important class of clinically used antibiotics. In response to this threat however, only a handful of β-lactamase inhibitors have been introduced to the market over the past thirty years. The first-generation β-lactamase inhibitors (clavulanic acid, sulbactam and tazobactam) are all β-lactam derivatives and work primarily by inactivating class A and some class C serine β-lactamases. The newer generations of β-lactamase inhibitors including avibactam and vaborbactam are based on non-β-lactam structures and their spectrum of inhibition is extended to KPC as an important class A carbapenemase. Despite these advances several class D and virtually all important class B β-lactamases are resistant to existing inhibitors. The present review provides an overview of recent FDA-approved β-lactam/β-lactamase inhibitor combinations as well as an update on research efforts aimed at the discovery and development of novel β-lactamase inhibitors.</p

A new tool to reveal bacterial signaling mechanisms in antibiotic treatment and resistance

The rapid emergence of antimicrobial resistance is a major threat to human health. Antibiotics modulate a wide range of biological processes in bacteria and as such, the study of bacterial cellular signaling could aid the development of urgently needed new antibiotic agents. Due to the advances in bacterial phosphoproteomics, such a systemwide analysis of bacterial signaling in response to antibiotics has recently become feasible. Here we present a dynamic view of differential protein phosphorylation upon antibiotic treatment and antibiotic resistance. Most strikingly, differential phosphorylation was observed on highly conserved residues of resistance regulating transcription factors, implying a previously unanticipated role of phosphorylation mediated regulation. Using the comprehensive phosphoproteomics data presented here as a resource, future research can now focus on deciphering the precise signaling mechanisms contributing to resistance, eventually leading to alternative strategies to combat antimicrobial resistance.FWN – Publicaties zonder aanstelling Universiteit Leide

Small molecule carboxylates inhibit metallo-β-lactamases and resensitize carbapenem-resistant bacteria to meropenem

Microbial Biotechnolog

Cephalosporin prodrug inhibitors overcome metallo‐β‐lactamase driven antibiotic resistance

Microbial Biotechnolog

De novo identification of lipid II binding lipopeptides with antibacterial activity against vancomycin-resistant bacteria

Creative strategies for identifying new antibiotics are essential to addressing the looming threat of a post-antibiotic era. We here report the use of a targeted peptide phage display screen as a means of generating novel antimicrobial lipopeptides. Specifically, a library of phage displayed bicyclic peptides was screened against a biomolecular target based on the bacterial cell wall precursor lipid II. In doing so we identified unique lipid II binding peptides that upon lipidation were found to be active against a range of Gram-positive bacteria including clinically relevant strains of vancomycin resistant bacteria. Optimization of the peptide sequence led to variants with enhanced antibacterial activity and reduced hemolytic activity. Biochemical experiments further confirm a lipid II mediated mode of action for these new-to-nature antibacterial lipopeptides.FWN – Publicaties zonder aanstelling Universiteit Leide

Probing the interaction of Aspergillomarasmine A (AMA) with metallo-β-lactamases NDM-1, VIM-2, and IMP-7

Metallo-β-lactamases (MBLs) are a growing threat to the continued efficacy of β-lactam antibiotics. Recently, aspergillomarasmine A (AMA) was identified as an MBL inhibitor, but the mode of inhibition was not fully characterized. Equilibrium dialysis and metal analysis studies revealed that 2 equiv of AMA effectively removes 1 equiv of Zn(II) from MBLs NDM-1, VIM-2, and IMP-7 when the MBL is at micromolar concentrations. Conversely, 1H NMR studies revealed that 2 equiv of AMA remove 2 equiv of Co(II) from Co(II)-substituted NDM-1, VIM-2, and IMP-7 when the MBL/AMA are at millimolar concentrations. Our findings reveal that AMA inhibits the MBLs by removal of the active site metal ions required for β-lactam hydrolysis among the most clinically significant MBLs.Microbial Biotechnolog