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Targeting class A and C serine ?-lactamases with a broad-spectrum boronic acid derivative.

ABSTRACT: Production of ?-lactamases (BLs) is the most widespread resistance mechanism adopted by bacteria to fight ?-lactam antibiotics. The substrate spectrum of BLs has become increasingly broad, posing a serious health problem. Thus, there is an urgent need for novel BL inhibitors. Boronic acid transition-state analogues are able to reverse the resistance conferred by class A and C BLs. We describe a boronic acid analogue possessing interesting and potent broad-spectrum activity vs class A and C serine-based BLs. Starting from benzo(b)thiophene-2-boronic acid (BZBTH2B), a nanomolar non-?-lactam inhibitor of AmpC that can potentiate the activity of a third-generation cephalosporin against AmpC-producing resistant bacteria, we designed a novel broad-spectrum nanomolar inhibitor of class A and C BLs. Structure-based drug design (SBDD), synthesis, enzymology data, and X-ray crystallography results are discussed. We clarified the inhibitor binding geometry responsible for broad-spectrum activity vs serine-active BLs using double mutant thermodynamic cycle studies.

SUBMITTER: Tondi D

PROVIDER: S-EPMC4079326 | biostudies-literature | 2014 Jun

REPOSITORIES: biostudies-literature

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Targeting class A and C serine β-lactamases with a broad-spectrum boronic acid derivative.

Tondi Donatella D Venturelli Alberto A Bonnet Richard R Pozzi Cecilia C Shoichet Brian K BK Costi Maria Paola MP

Journal of medicinal chemistry 20140616 12

Production of β-lactamases (BLs) is the most widespread resistance mechanism adopted by bacteria to fight β-lactam antibiotics. The substrate spectrum of BLs has become increasingly broad, posing a serious health problem. Thus, there is an urgent need for novel BL inhibitors. Boronic acid transition-state analogues are able to reverse the resistance conferred by class A and C BLs. We describe a boronic acid analogue possessing interesting and potent broad-spectrum activity vs class A and C serin ...[more]

PMID: 24882105

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Project description:As shifts in the epidemiology of ?-lactamase-mediated resistance continue, carbapenem-resistant Enterobacterales (CRE) and carbapenem-resistant Pseudomonas aeruginosa (CRPA) are the most urgent threats. Although approved ?-lactam (BL)-?-lactamase inhibitor (BLI) combinations address widespread serine ?-lactamases (SBLs), such as CTX-M-15, none provide broad coverage against either clinically important serine-?-lactamases (KPC, OXA-48) or clinically important metallo-?-lactamases (MBLs; e.g., NDM-1). VNRX-5133 (taniborbactam) is a new cyclic boronate BLI that is in clinical development combined with cefepime for the treatment of infections caused by ?-lactamase-producing CRE and CRPA. Taniborbactam is the first BLI with direct inhibitory activity against Ambler class A, B, C, and D enzymes. From biochemical and structural analyses, taniborbactam exploits substrate mimicry while employing distinct mechanisms to inhibit both SBLs and MBLs. It is a reversible covalent inhibitor of SBLs with slow dissociation and a prolonged active-site residence time (half-life, 30 to 105?min), while in MBLs, it behaves as a competitive inhibitor, with inhibitor constant (Ki ) values ranging from 0.019 to 0.081??M. Inhibition is achieved by mimicking the transition state structure and exploiting interactions with highly conserved active-site residues. In microbiological testing, taniborbactam restored cefepime activity in 33/34 engineered Escherichia coli strains overproducing individual enzymes covering Ambler classes A, B, C, and D, providing up to a 1,024-fold shift in the MIC. Addition of taniborbactam restored the antibacterial activity of cefepime against all 102 Enterobacterales clinical isolates tested and 38/41 P. aeruginosa clinical isolates tested with MIC90s of 1 and 4??g/ml, respectively, representing ?256- and ?32-fold improvements, respectively, in antibacterial activity over that of cefepime alone. The data demonstrate the potent, broad-spectrum rescue of cefepime activity by taniborbactam against clinical isolates of CRE and CRPA.

Dataset Information

Targeting class A and C serine ?-lactamases with a broad-spectrum boronic acid derivative.

Publications

Targeting class A and C serine β-lactamases with a broad-spectrum boronic acid derivative.

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