211623-25-5Relevant academic research and scientific papers
6-Arylmethylidene Penicillin-Based Sulfone Inhibitors for Repurposing Antibiotic Efficiency in Priority Pathogens
Rodríguez, Diana,Maneiro, María,Vázquez-Ucha, Juan C.,Beceiro, Alejandro,González-Bello, Concepción
, p. 3737 - 3755 (2020/04/30)
The ability of 6-(aryl)methylidene penicillin-based sulfones 1-7 to repurpose β-lactam antibiotics activity with bacterial species that carry carbapenem-hydrolyzing class D β-lactamases (OXA-23, OXA-24/40 and OXA-48), as well as with class A (TEM-1, CTX-M-2) and class C (CMY-2, DHA-1) enzymes, is reported. The combinations imipenem/3 and imipenem/4 restored almost completely the antibiotic efficacy in OXA-23 and OXA-24/40 carbapenemase-producing A. baumannii strains (1 μg mL-1) and also provided good results for OXA-48 carbapenemase-producing K. pneumoniae strains (4 μg mL-1). Compounds 2-6 in combinations with ceftazidime and ampicillin were also efficient in restoring antibiotic efficacy in E. coli strains carrying class C (CMY-2 and DHA-1) and class A (TEM-1 and CTX-M-2) β-lactamase enzymes, respectively. Kinetic and inhibition studies with the OXA-24/40 enzyme, protein mass spectrometry analysis and docking studies allowed us to gain an insight into the inhibition mechanism and the experimentally observed differences between the ligands.
BETA-LACTAMASE INHIBITORY COMPOUNDS
-
Page/Page column 11; 12, (2010/02/17)
Inhibitors of the enzyme beta-lactamase are provided. The compounds are adapted to inhibit beta-lactamase as produced by beta-lactam resistant bacterial strains. Methods of treatment of beta-lactam resistant bacterial infections in patients are provided.
Design, synthesis, and crystal structures of 6-alkylidene-2′- substituted penicillanic acid sulfones as potent inhibitors of acinetobacter baumannii OXA-24 carbapenemase
Bou, German,Santillana, Elena,Sheri, Anjaneyulu,Beceiro, Alejandro,Sampson, Jared M.,Kalp, Matthew,Bethel, Christopher R.,Distler, Anne M.,Drawz, Sarah M.,Pagadala, Sundar Ram Reddy,Van Den Akker, Focco,Bonomo, Robert A.,Romero, Antonio,Buynak, John D.
supporting information; scheme or table, p. 13320 - 13331 (2010/12/18)
Class D β-lactamases represent a growing and diverse class of penicillin-inactivating enzymes that are usually resistant to commercial β-lactamase inhibitors. As many such enzymes are found in multi-drug resistant (MDR) Acinetobacter baumannii and Pseudomonas aeruginosa, novel β-lactamase inhibitors are urgently needed. Five unique 6-alkylidene-2′-substituted penicillanic acid sulfones (1-5) were synthesized and tested against OXA-24, a clinically important β-lactamase that inactivates carbapenems and is found in A. baumannii. Based upon the roles Tyr112 and Met223 play in the OXA-24 β-lactamase, we also engineered two variants (Tyr112Ala and Tyr112Ala,Met223Ala) to test the hypothesis that the hydrophobic tunnel formed by these residues influences inhibitor recognition. IC50 values against OXA-24 and two OXA-24 β-lactamase variants ranged from 10 ± 1 (4 vs WT) to 338 ± 20 nM (5 vs Tyr112Ala, Met223Ala). Compound 4 possessed the lowest Ki (500 ± 80 nM vs WT), and 1 possessed the highest inactivation efficiency (kinact/ Ki = 0.21 ± 0.02 μM-1 s-1). Electrospray ionization mass spectrometry revealed a single covalent adduct, suggesting the formation of an acyl-enzyme intermediate. X-ray structures of OXA-24 complexed to four inhibitors (2.0-2.6 A) reveal the formation of stable bicyclic aromatic intermediates with their carbonyl oxygen in the oxyanion hole. These data provide the first structural evidence that 6-alkylidene-2′-substituted penicillin sulfones are effective mechanism-based inactivators of class D β-lactamases. Their unique chemistry makes them developmental candidates. Mechanisms for class D hydrolysis and inhibition are discussed, and a pathway for the evolution of the BlaR1 sensor of Staphylococcus aureus to the class D β-lactamases is proposed.
The synthesis and evaluation of 6-alkylidene-2'β-substituted penam sulfones as β-lactamase inhibitors
Buynak, John D.,A Srinivasa, Rao,Doppalapudi, Venkata Ramana,Adam, Greg,Petersen, Peter J.,Nidamarthy, Sirishkumar D.
, p. 1997 - 2002 (2007/10/03)
Penicillin sulfones, which structurally incorporate both a 6-position alkylidene substituent and a 2'β substituent, have been synthesized and evaluated as inhibitors of class C and class A serine β-lactamases. Incorporation of the 2'β-substituent generall
