scholarly journals Modified Penicillin Molecule with Carbapenem-Like Stereochemistry Specifically Inhibits Class C β-Lactamases

2017 ◽  
Vol 61 (12) ◽  
Author(s):  
Xuehua Pan ◽  
Yunjiao He ◽  
Tianfeng Chen ◽  
Kin-Fai Chan ◽  
Yanxiang Zhao
Keyword(s):  
Active Site ◽  
Binding Mode ◽  
Carboxyl Group ◽  
Hydrogen Atoms ◽  
Chemical Modifications ◽  
Inhibitory Potency ◽  
Current Collection ◽  
Class A ◽  
Lactam Ring ◽  
Class C

ABSTRACT Bacterial β-lactamases readily inactivate most penicillins and cephalosporins by hydrolyzing and “opening” their signature β-lactam ring. In contrast, carbapenems resist hydrolysis by many serine-based class A, C, and D β-lactamases due to their unique stereochemical features. To improve the resistance profile of penicillins, we synthesized a modified penicillin molecule, MPC-1, by “grafting” carbapenem-like stereochemistry onto the penicillin core. Chemical modifications include the trans conformation of hydrogen atoms at C-5 and C-6 instead of cis, and a 6-α hydroxyethyl moiety to replace the original 6-β aminoacyl group. MPC-1 selectively inhibits class C β-lactamases, such as P99, by forming a nonhydrolyzable acyl adduct, and its inhibitory potency is ∼2 to 5 times higher than that for clinically used β-lactamase inhibitors clavulanate and sulbactam. The crystal structure of MPC-1 forming the acyl adduct with P99 reveals a novel binding mode for MPC-1 that resembles carbapenem bound in the active site of class A β-lactamases. Furthermore, in this novel binding mode, the carboxyl group of MPC-1 blocks the deacylation reaction by occluding the critical catalytic water molecule and renders the acyl adduct nonhydrolyzable. Our results suggest that by incorporating carbapenem-like stereochemistry, the current collection of over 100 penicillins and cephalosporins can be modified into candidate compounds for development of novel β-lactamase inhibitors.

scholarly journals GMP and IMP Are Competitive Inhibitors of CMY-10, an Extended-Spectrum Class C β-Lactamase

2017 ◽  
Vol 61 (5) ◽  
Author(s):  
Jung-Hyun Na ◽  
Young Jun An ◽  
Sun-Shin Cha
Keyword(s):  
Crystal Structure ◽  
Active Site ◽  
Binding Mode ◽  
Competitive Inhibitor ◽  
Phosphate Group ◽  
The Other ◽  
Extended Spectrum ◽  
Competitive Inhibitors ◽  
Class C

ABSTRACT Nucleotides were effective in inhibiting the class C β-lactamase CMY-10. IMP was the most potent competitive inhibitor, with a Ki value of 16.2 μM. The crystal structure of CMY-10 complexed with GMP or IMP revealed that nucleotides fit into the R2 subsite of the active site with a unique vertical binding mode where the phosphate group at one terminus is deeply bound in the subsite and the base at the other terminus faces the solvent.

scholarly journals Bicyclic Boronates as Potent Inhibitors of AmpC, the Class C β-Lactamase from Escherichia coli

Biomolecules ◽  
2020 ◽  
Vol 10 (6) ◽  
pp. 899 ◽  
Author(s):  
Pauline A. Lang ◽  
Anete Parkova ◽  
Thomas M. Leissing ◽  
Karina Calvopiña ◽  
Ricky Cain ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Active Site ◽  
High Energy ◽  
Structural Basis ◽  
Side Chain ◽  
Class A ◽  
Dual Action ◽  
Class C ◽  
Tract Infections ◽  
Site Binding

Resistance to β-lactam antibacterials, importantly via production of β-lactamases, threatens their widespread use. Bicyclic boronates show promise as clinically useful, dual-action inhibitors of both serine- (SBL) and metallo- (MBL) β-lactamases. In combination with cefepime, the bicyclic boronate taniborbactam is in phase 3 clinical trials for treatment of complicated urinary tract infections. We report kinetic and crystallographic studies on the inhibition of AmpC, the class C β-lactamase from Escherichia coli, by bicyclic boronates, including taniborbactam, with different C-3 side chains. The combined studies reveal that an acylamino side chain is not essential for potent AmpC inhibition by active site binding bicyclic boronates. The tricyclic form of taniborbactam was observed bound to the surface of crystalline AmpC, but not at the active site, where the bicyclic form was observed. Structural comparisons reveal insights into why active site binding of a tricyclic form has been observed with the NDM-1 MBL, but not with other studied β-lactamases. Together with reported studies on the structural basis of inhibition of class A, B and D β-lactamases, our data support the proposal that bicyclic boronates are broad-spectrum β-lactamase inhibitors that work by mimicking a high energy ‘tetrahedral’ intermediate. These results suggest further SAR guided development could improve the breadth of clinically useful β-lactamase inhibition.

scholarly journals Active-Site Protonation States in an Acyl-Enzyme Intermediate of a Class A β-Lactamase with a Monobactam Substrate

2016 ◽  
Vol 61 (1) ◽  
Author(s):  
Venu Gopal Vandavasi ◽  
Patricia S. Langan ◽  
Kevin L. Weiss ◽  
Jerry M. Parks ◽  
Jonathan B. Cooper ◽  
...  
Keyword(s):  
Active Site ◽  
Catalytic Mechanism ◽  
Active Site Residues ◽  
Hydrogen Atoms ◽  
Content Type ◽  
X Ray Crystallography ◽  
General Base ◽  
Class A ◽  
Extended Spectrum ◽  
Enzyme Intermediate

ABSTRACT The monobactam antibiotic aztreonam is used to treat cystic fibrosis patients with chronic pulmonary infections colonized by Pseudomonas aeruginosa strains expressing CTX-M extended-spectrum β-lactamases. The protonation states of active-site residues that are responsible for hydrolysis have been determined previously for the apo form of a CTX-M β-lactamase but not for a monobactam acyl-enzyme intermediate. Here we used neutron and high-resolution X-ray crystallography to probe the mechanism by which CTX-M extended-spectrum β-lactamases hydrolyze monobactam antibiotics. In these first reported structures of a class A β-lactamase in an acyl-enzyme complex with aztreonam, we directly observed most of the hydrogen atoms (as deuterium) within the active site. Although Lys 234 is fully protonated in the acyl intermediate, we found that Lys 73 is neutral. These findings are consistent with Lys 73 being able to serve as a general base during the acylation part of the catalytic mechanism, as previously proposed.

scholarly journals The Role of the Ω-Loop in Regulation of the Catalytic Activity of TEM-Type β-Lactamases

Biomolecules ◽  
2019 ◽  
Vol 9 (12) ◽  
pp. 854 ◽  
Author(s):  
Alexey Egorov ◽  
Maya Rubtsova ◽  
Vitaly Grigorenko ◽  
Igor Uporov ◽  
Alexander Veselovsky
Keyword(s):  
Active Site ◽  
Bacterial Resistance ◽  
Structural Flexibility ◽  
Allosteric Inhibitors ◽  
Penicillin Binding Proteins ◽  
Global Challenge ◽  
Class A ◽  
Lactam Ring ◽  
Hydrolysis Of

Bacterial resistance to β-lactams, the most commonly used class of antibiotics, poses a global challenge. This resistance is caused by the production of bacterial enzymes that are termed β-lactamases (βLs). The evolution of serine-class A β-lactamases from penicillin-binding proteins (PBPs) is related to the formation of the Ω-loop at the entrance to the enzyme’s active site. In this loop, the Glu166 residue plays a key role in the two-step catalytic cycle of hydrolysis. This residue in TEM–type β-lactamases, together with Asn170, is involved in the formation of a hydrogen bonding network with a water molecule, leading to the deacylation of the acyl–enzyme complex and the hydrolysis of the β-lactam ring of the antibiotic. The activity exhibited by the Ω-loop is attributed to the positioning of its N-terminal residues near the catalytically important residues of the active site. The structure of the Ω-loop of TEM-type β-lactamases is characterized by low mutability, a stable topology, and structural flexibility. All of the revealed features of the Ω-loop, as well as the mechanisms related to its involvement in catalysis, make it a potential target for novel allosteric inhibitors of β-lactamases.

An active-site peptide containing the second essential carboxyl group of dextransucrase from Leuconostoc mesenteroides by chemical modifications

Biochemistry ◽  
1993 ◽  
Vol 32 (49) ◽  
pp. 13696-13702 ◽  
Author(s):  
Kazumi Funane ◽  
Masakazu Shiraiwa ◽  
Kenya Hashimoto ◽  
Eiji Ichishima ◽  
Mikihiko Kobayashi
Keyword(s):  
Active Site ◽  
Leuconostoc Mesenteroides ◽  
Carboxyl Group ◽  
Chemical Modifications

scholarly journals Effect of the 3′-leaving group on turnover of cephem antibiotics by a class C β-lactamase

1989 ◽  
Vol 259 (1) ◽  
pp. 255-260 ◽  
Author(s):  
L J Mazzella ◽  
R F Pratt
Keyword(s):  
Active Site ◽  
First Generation ◽  
Enterobacter Cloacae ◽  
Beta Lactamase ◽  
Beta Lactamases ◽  
Class A ◽  
Leaving Group ◽  
Enzyme Intermediates ◽  
Class C ◽  
Third Generation Cephalosporins

It has been previously demonstrated for class A beta-lactamases and the DD-peptidase of Streptomyces R61 that the presence of a leaving group at the 3′-position of a cephalosporin can lead to the generation of more-inert acyl-enzyme intermediates than from cephalosporins lacking such a leaving group, and thus to beta-lactamase inhibitors and potentially better antibiotics. In the present work we extend this result to a class C beta-lactamase, that of Enterobacter cloacae P99. The effect is not seen with first-generation cephalosporins, since here deacylation generally seems faster than elimination of the leaving group, but it does clearly appear with cephamycins and third-generation cephalosporins. The structural and/or mechanistic features of the active site giving rise to this phenomenon may thus be common to all serine beta-lactamases and transpeptidases.

scholarly journals Some kinematics of halo coronal mass ejections

2020 ◽  
Vol 29 (1) ◽  
pp. 81-88
Author(s):  
Virendra Kumar Verma ◽  
Nishant Mittal ◽  
Ramesh Chandra
Keyword(s):  
Coronal Mass Ejections ◽  
Solar Flares ◽  
Coronal Holes ◽  
Geomagnetic Disturbances ◽  
Class A ◽  
Heliospheric Physics ◽  
Class B ◽  
The Mean ◽  
Class C

AbstractWe present an investigation of halo coronal mass ejections (HCMEs) kinematics and other facts about the HCMEs. The study of HCMEs is very important because HCMEs are regarded as the main causes of heliospheric and geomagnetic disturbances. In this study, we have investigated 313 HCMEs observed during 1996-2012 by LASCO, coronal holes, and solar flares. We find that HCMEs are of two types: accelerated HCMEs and decelerated HCMEs. The mean space speed of HCMEs is 1283 km/s while the mean speed of decelerated HCMEs and accelerated HCMEs is 1349 km/s and 1174 km/s, respectively. The investigation shows that 1 (0.3%) HCME was associated with class A SXR, 14 (4.7%) HCMEs were associated with class B SXR-flares, 87 (29.4%) HCMEs were associated with class C SXR-flares, 125 (42.2%) HCMEs were associated with class M SXR-flares and 69 (23.3%) HCMEs were associated with class X SXR-flares. The speed of HCMEs increases with the importance of solar SXR-flares. The various results obtained in the present analysis are discussed in the light of the existing scenario of heliospheric physics.

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