4,7-Dichloro benzothien-2-yl sulfonylaminomethyl boronic acid: First boronic acid-derived beta-lactamase inhibitor with class A, C, and D activity

Tan, Qiang; Ogawa, Aimie M.; Painter, Ronald E.; Park, Young-Whan; Young, Katherine; DiNinno, Frank

doi:10.1016/j.bmcl.2010.02.065

Cited by 28 publications

(25 citation statements)

References 13 publications

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“…As revealed by a crystal structure of the CTX-M-15-avibactam complex [161], the nitrogen of the N-sulfate group of the ring opened avibactam and a [149], 10.2, 10.3 [150], 10.4 [148], 10.5 [151], 10.6 [152], 10.7 [148] and 10.8 [153]). (B) Examples of 'new' β-lactam scaffolds also show promise, but they have not been commercially developed (AM-112 (10.9) [154] and LK-157 (10.10) [155]).…”

Section: Avibactam Mode Of Actionmentioning

confidence: 99%

The Road to Avibactam: The First Clinically Useful Non-β-Lactam Working Somewhat Like a β-Lactam

et al. 2016

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Avibactam, which is the first non-β-lactam β-lactamase inhibitor to be introduced for clinical use, is a broad-spectrum serine β-lactamase inhibitor with activity against class A, class C, and, some, class D β-lactamases. We provide an overview of efforts, which extend to the period soon after the discovery of the penicillins, to develop clinically useful non-β-lactam compounds as antibacterials, and, subsequently, penicillin-binding protein and β-lactamase inhibitors. Like the β-lactam inhibitors, avibactam works via a mechanism involving covalent modification of a catalytically important nucleophilic serine residue. However, unlike the β-lactam inhibitors, avibactam reacts reversibly with its β-lactamase targets. We discuss chemical factors that may account for the apparently special nature of β-lactams and related compounds as antibacterials and β-lactamase inhibitors, including with respect to resistance. Avenues for future research including non-β-lactam antibacterials acting similarly to β-lactams are discussed.

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Section: Avibactam Mode Of Actionmentioning

confidence: 99%

The Road to Avibactam: The First Clinically Useful Non-β-Lactam Working Somewhat Like a β-Lactam

et al. 2016

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“…In 2010, medicinal chemists reported on a 4,7-dichloro-1-benzothien-2-yl sulfonylaminomethyl (DSABA) compound with a 5.6 M IC 50 against OXA-24/40 ( Fig. 6c) (109). DSABA also inhibits class A and C ␤-lactamases with low-M IC 50 s (i.e., 0.57 and 1.1 M for SHV-5 and TEM-1 and 0.62 and 1.2 M for P99 and P. aeruginosa AmpC, respectively).…”

Section: Class D ␤-Lactamases; Anticipating a Growing Needmentioning

confidence: 99%

New β-Lactamase Inhibitors: a Therapeutic Renaissance in an MDR World

Drawz

Papp-Wallace

Bonomo

2014

Antimicrob Agents Chemother

263

179

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As the incidence of Gram-negative bacterial infections for which few effective treatments remain increases, so does the contribution of drug-hydrolyzing ␤-lactamase enzymes to this serious clinical problem. This review highlights recent advances in ␤-lactamase inhibitors and focuses on agents with novel mechanisms of action against a wide range of enzymes. To this end, we review the ␤-lactamase inhibitors currently in clinical trials, select agents still in preclinical development, and older therapeutic approaches that are being revisited. Particular emphasis is placed on the activity of compounds at the forefront of the developmental pipeline, including the diazabicyclooctane inhibitors (avibactam and MK-7655) and the boronate RPX7009. With its novel reversible mechanism, avibactam stands to be the first new ␤-lactamase inhibitor brought into clinical use in the past 2 decades. Our discussion includes the importance of selecting the appropriate partner ␤-lactam and dosing regimens for these promising agents. This "renaissance" of ␤-lactamase inhibitors offers new hope in a world plagued by multidrug-resistant (MDR) Gram-negative bacteria.

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“…More recently several thiophenyl oxime-derived phosphonates were reported as inhibitors for OXA-24/40 (IC 50 s 17 μM and 31 μM) that exhibited synergy in combination with imipenem 67 . A recent paper reported 4,7-dichloro-1-benzothien-2-yl-sufonyl-aminomethyl boronic acid as the first boronic acid-based class D β-lactamase inhibitor with activity against OXA-24 (IC 50 5.6 μM) 68 .…”

Section: Prospects For Drug Developmentmentioning

confidence: 99%

Class D β-Lactamases: A Reappraisal after Five Decades

2013

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Conspectus Despite 70 years of clinical use, β-lactam antibiotics still remain at the forefront of antimicrobial chemotherapy. The major challenge to these life-saving therapeutics is the presence of bacterial enzymes (i.e., β-lactamases) that can hydrolyze the β-lactam bond and inactivate the antibiotic. These enzymes can be grouped into 4 classes (A-D). Among the most genetically diverse are the class D β-lactamases. In this class are β-lactamases that can inactivate the entire spectrum of β- lactam antibiotics (penicillins, cephalosporins, and carbapenems). Class D β-lactamases are mostly found in Gram-negative bacteria such as Pseudomonas aeruginosa, Escherichia coli, Proteus mirabilis, and Acinetobacter baumannii. The active-sites of class D β-lactamases contain an unusual N-carboxylated lysine post-translational modification. A strongly hydrophobic active-site helps create the conditions that allow the lysine to combine with CO2, and the resulting carbamate is stabilized by a number of hydrogen bonds. The carboxy-lysine plays a symmetric role in the reaction, serving as a general base to activate the serine nucleophile in the acylation reaction, and the deacylating water in the second step. There are more than 250 class D β-lactamases described, and the full set of variants shows remarkable diversity with regard to substrate binding and turnover. Narrow-spectrum variants are most effective against the earliest generation penicillins and cephalosporins such as ampicillin and cephalothin. Extended-spectrum variants (also known as extended-spectrum β-lactamases, ESBLs) pose a more dangerous clinical threat as they possess a small number of substitutions that allow them to bind and hydrolyze later generation cephalosporins that contain bulkier side-chain constituents (eg. cefotaxime, ceftazidime, and cefepime). Mutations that permit this versatility seem to cluster in the area surrounding an active-site tryptophan resulting in a widened active-site to accommodate the oxyimino side-chains of these cephalosporins. More concerning are the class D β-lactamases that hydrolyze clinically-important carbapenem β-lactam drugs (e.g., imipenem). Whereas carbapenems irreversibly acylate and inhibit narrow- spectrum β-lactamases, class D carbapenemases are able to recruit and activate a deacylating water. The rotational orientation of the C6 hydroxyethyl group found on all carbapenem antibiotics likely plays a role in whether the deacylating water is effective or not. Inhibition of class D β-lactamases is a current challenge. Commercially available inhibitors that are active against other classes of β-lactamases are ineffective against class D enzymes. On the horizon are several compounds, consisting of both β-lactam derivatives and non-β-lactams, that have the potential of providing novel leads to design new mechanism-based inactivators that are effective against the class D enzymes. Several act synergistically when given in combination with a β-lactam antibiotic, and others show a unique mechanism of inhibition that is d...

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4,7-Dichloro benzothien-2-yl sulfonylaminomethyl boronic acid: First boronic acid-derived beta-lactamase inhibitor with class A, C, and D activity

Cited by 28 publications

References 13 publications

The Road to Avibactam: The First Clinically Useful Non-β-Lactam Working Somewhat Like a β-Lactam

The Road to Avibactam: The First Clinically Useful Non-β-Lactam Working Somewhat Like a β-Lactam

New β-Lactamase Inhibitors: a Therapeutic Renaissance in an MDR World

Class D β-Lactamases: A Reappraisal after Five Decades

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