Cyclic boronates as versatile scaffolds for KPC-2 β-lactamase inhibition
Catherine L Tooke1,2, Philip Hinchliffe1, Alen Krajnc3
1School of Cellular and Molecular Medicine , Biomedical Sciences Building , University of Bristol , Bristol , BS8 1TD , UK .
RSC Medicinal Chemistry
|January 22, 2021
Summary
Vaborbactam and taniborbactam both inhibit Klebsiella pneumoniae carbapenemase-2 (KPC-2). Taniborbactam offers stronger, longer-lasting inhibition, suggesting potential for improved treatments against KPC-2 resistant bacteria.
Area of Science:
- Biochemistry
- Microbiology
- Pharmacology
Background:
- Klebsiella pneumoniae carbapenemase-2 (KPC-2) is a critical enzyme conferring resistance to beta-lactam antibiotics.
- The emergence of KPC-2 necessitates the development of novel inhibitory agents.
Purpose of the Study:
- To compare the inhibitory activity of vaborbactam and taniborbactam against KPC-2.
- To elucidate the binding mechanisms of these inhibitors using X-ray crystallography.
Main Methods:
- Enzyme inhibition assays to determine on- and off-rates.
- High-resolution X-ray crystallography to visualize inhibitor-enzyme complexes.
- Assessment of beta-lactam potentiation against KPC-2 expressing K. pneumoniae.
Main Results:
- Both vaborbactam (monocyclic boronate) and taniborbactam (bicyclic boronate) inhibit KPC-2.
- Taniborbactam exhibits a significantly higher on-rate and slower off-rate, indicating more potent and sustained inhibition compared to vaborbactam.
- X-ray structures show similar binding modes, with subtle differences in the boronate ester oxygen positioning.
Conclusions:
- The bicyclic boronate scaffold, exemplified by taniborbactam, represents a highly effective and durable KPC-2 inhibitor.
- Further structural optimization of bicyclic boronates may enhance potency and overcome emerging resistance mechanisms.
Related Concept Videos
02:47Alkynes to Aldehydes and Ketones: Hydroboration-Oxidation
19.8K
Introduction
One of the convenient methods for the preparation of aldehydes and ketones is via hydration of alkynes. Hydroboration-oxidation of alkynes is an indirect hydration reaction in which an alkyne is treated with borane followed by oxidation with alkaline peroxide to form an enol that rapidly converts into an aldehyde or a ketone. Terminal alkynes form aldehydes, whereas internal alkynes give ketones as the final product.
One of the convenient methods for the preparation of aldehydes and ketones is via hydration of alkynes. Hydroboration-oxidation of alkynes is an indirect hydration reaction in which an alkyne is treated with borane followed by oxidation with alkaline peroxide to form an enol that rapidly converts into an aldehyde or a ketone. Terminal alkynes form aldehydes, whereas internal alkynes give ketones as the final product.
19.8K
02:36Regioselectivity and Stereochemistry of Hydroboration
8.9K
A significant aspect of hydroboration–oxidation is the regio- and stereochemical outcome of the reaction.
Hydroboration proceeds in a concerted fashion with the attack of borane on the π bond, giving a cyclic four-centered transition state. The –BH2 group is bonded to the less substituted carbon and –H to the more substituted carbon. The concerted nature requires the simultaneous addition of –H and –BH2 across the same face of the alkene giving syn stereochemistry.
Hydroboration proceeds in a concerted fashion with the attack of borane on the π bond, giving a cyclic four-centered transition state. The –BH2 group is bonded to the less substituted carbon and –H to the more substituted carbon. The concerted nature requires the simultaneous addition of –H and –BH2 across the same face of the alkene giving syn stereochemistry.
8.9K
01:29Diels–Alder Reaction Forming Bridged Bicyclic Products: Stereochemistry
5.0K
Diels–Alder reactions between cyclic dienes locked in an s-cis configuration and dienophiles yield bridged bicyclic products.
5.0K
03:08Hydroboration-Oxidation of Alkenes
10.0K
In addition to the oxymercuration–demercuration method, which converts the alkenes to alcohols with Markovnikov orientation, a complementary hydroboration-oxidation method yields the anti-Markovnikov product. The hydroboration reaction, discovered in 1959 by H.C. Brown, involves the addition of a B–H bond of borane to an alkene giving an organoborane intermediate. The oxidation of this intermediate with basic hydrogen peroxide forms an alcohol.
10.0K
01:22Reactions of Aldehydes and Ketones: Baeyer–Villiger Oxidation
4.6K
Baeyer–Villiger oxidation converts aldehydes to carboxylic acids and ketones to esters. The reaction uses peroxy acids or peracids and is often catalyzed by acid. The reaction is named after its pioneers, Adolf von Baeyer and Victor Villiger. The reaction is achieved by a wide range of peracids such as m-chloroperoxybenzoic acid (mCPBA), perbenzoic acid (C6H5COOOH), peracetic acid (CH3COOOH), hydrogen peroxide (H2O2), and tert-butyl hydroperoxide (t-BuOOH).
The carbonyl center is activated by...
The carbonyl center is activated by...
4.6K
01:10α-Alkylation of Ketones via Enolate Ions
3.6K
Ketones with α protons are deprotonated by strong bases like lithium diisopropylamide (LDA) to form enolate ions. The anion is stabilized by resonance, and its hybrid structure exhibits negative charges on the carbonyl oxygen and the α carbon. This ambident nucleophile can attack an electrophile via two possible sites: the carbonyl oxygen, known as O-attack, or the α carbon, known as C-attack. The nucleophilic attack via the carbanionic site is preferred. This is due to the...
3.6K