Efficacy of aspergillomarasmine A/meropenem combinations with and without avibactam against bacterial strains producing multiple β-lactamases.

The effectiveness of β-lactam antibiotics is increasingly threatened by resistant bacteria that harbor hydrolytic β-lactamase enzymes. Depending on the class of β-lactamase present, β-lactam hydrolysis can occur through one of two general molecular mechanisms. Metallo-β-lactamases (MBLs) require active site Zn ions, whereas serine-β-lactamases (SBLs) deploy a catalytic serine residue.

Three-Dimensional Structure and Optimization of the Metallo-β-Lactamase Inhibitor Aspergillomarasmine A.

The aminopolycarboxylic acid aspergillomarasmine A (AMA) is a natural Zn metallophore and inhibitor of metallo-β-lactamases (MBLs) which reverses β-lactam resistance. The first crystal structure of an AMA coordination complex is reported and reveals a pentadentate ligand with distorted octahedral geometry. We report the solid-phase synthesis of 23 novel analogs of AMA involving structural diversification of each subunit (l-Asp, l-APA1, and l-APA2).

Aspergillomarasmine A inhibits metallo-β-lactamases by selectively sequestering Zn.

Class B metallo-β-lactamases (MBLs) are Zn-dependent enzymes that catalyze the hydrolysis of β-lactam antibiotics to confer resistance in bacteria. Several problematic groups of MBLs belong to subclass B1, including the binuclear New Delhi MBL (NDM), Verona integrin-encoded MBL, and imipenemase-type enzymes, which are responsible for widespread antibiotic resistance. Aspergillomarasmine A (AMA) is a natural aminopolycarboxylic acid that functions as an effective inhibitor of class B1 MBLs.

Suppression of β-Lactam Resistance by Aspergillomarasmine A Is Influenced by both the Metallo-β-Lactamase Target and the Antibiotic Partner.

The rise of Gram-negative pathogens expressing metallo-β-lactamases (MBLs) is a growing concern, threatening the efficacy of β-lactam antibiotics, in particular, the carbapenems. There are no inhibitors of MBLs in current clinical use. Aspergillomarasmine A (AMA) is an MBL inhibitor isolated from with the ability to rescue meropenem activity in MBL-producing bacteria both and Here, we systematically explored the pairing of AMA with six β-lactam antibiotic partners against 19 MBLs from three subclasses (B1, B2, and B3).

Inhibitors of metallo-β-lactamases.

The β-lactams are the most successful class of antibiotic drugs but they are vulnerable to inactivation by a growing cadre of β-lactamases that now number more than a thousand variants. β-Lactamases operate by one of two general chemical mechanisms either catalyzing β-lactam ring hydrolysis via a covalent enzyme intermediate through the aegis of an active site serine residue or through a noncovalent Zn-dependent mechanism. The Ser-β-lactamases are currently dominant in the clinic and consequently, there has been great effort to identify inhibitors and to co-formulate these with β-lactam antibiotics.

Arginine-containing peptides as potent inhibitors of VIM-2 metallo-β-lactamase.

Background: Metallo-β-lactamases (MBLs) play an important role in the emergence of microbial resistance to β-lactam antibiotics, and are hence considered targets for the design of novel therapeutics. We here report on the inhibitory effect of peptides containing multiple arginine residues on VIM-2, a clinically important MBL from Pseudomonas aeruginosa.

Methods: Enzyme kinetic assays in combination with fluorescence spectroscopy and stopped-flow UV-Vis spectrophotometry were utilized to explore the structure-activity relationship of peptides as inhibitors of VIM-2.