- 6-Arylmethylidene Penicillin-Based Sulfone Inhibitors for Repurposing Antibiotic Efficiency in Priority Pathogens
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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.
- Rodríguez, Diana,Maneiro, María,Vázquez-Ucha, Juan C.,Beceiro, Alejandro,González-Bello, Concepción
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p. 3737 - 3755
(2020/04/30)
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- Modifications of the C6-substituent of penicillin sulfones with the goal of improving inhibitor recognition and efficacy
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In order to evaluate the importance of a hydrogen-bond donating substituent in the design of β-lactamase inhibitors, a series of C6-substituted penicillin sulfones, lacking a C2′ substituent, and having an sp 3 hybridized C6, was prepared and evaluated against a representative classes A and C β-lactamases. It was found that a C6 hydrogen-bond donor is necessary for good inhibitory activity, but that this feature alone is not sufficient in this series of C6β-substituted penicillin sulfones. Other factors which may impact the potency of the inhibitor include the steric bulk of the C6 substituent (e.g., methicillin sulfone) which may hinder recognition in the class A β-lactamases, and also high similarity to the natural substrates (e.g., penicillin G sulfone) which may render the prospective inhibitor a good substrate of both classes of enzyme. The best inhibitors had non-directional hydrogen-bonding substituents, such as hydroxymethyl, which may allow sufficient conformational flexibility of the acyl-enzyme for abstraction of the C6 proton by E166 (class A), thus promoting isomerization to the β-aminoacrylate as a stabilized acyl-enzyme.
- Nottingham, Micheal,Bethel, Christopher R.,Pagadala, Sundar Ram Reddy,Harry, Emily,Pinto, Abishai,Lemons, Zachary A.,Drawz, Sarah M.,Akker, Focco Van Den,Carey, Paul R.,Bonomo, Robert A.,Buynak, John D.
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scheme or table
p. 387 - 393
(2011/03/17)
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- Design, synthesis, and crystal structures of 6-alkylidene-2′- substituted penicillanic acid sulfones as potent inhibitors of acinetobacter baumannii OXA-24 carbapenemase
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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.
- 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.
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supporting information; scheme or table
p. 13320 - 13331
(2010/12/18)
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- BETA-LACTAMASE INHIBITORY COMPOUNDS
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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.
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Page/Page column 10; 11
(2010/02/17)
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- Penicillin-derived inhibitors that simultaneously target both metallo- and serine-β-lactamases
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The synthesis and β-lactamase inhibitory activity of four 6-(mercaptomethyl)penicillinates and the four corresponding 6-(hydroxymethyl) penicillinates are described. These penicillins include both C6 stereoisomers as well as the sulfide and sulfone oxidation states of the penam thiazolidine sulfur. All compounds were evaluated as inhibitors of representative metallo- and serine-β-lactamases enzymes. Selected (mercaptomethyl)penicillinates are shown to inactivate both metallo- and serine-β-lactamases and to display synergism with piperacillin against β-lactamase producing strains.
- Buynak, John D.,Chen, Hansong,Vogeti, Lakshminaryana,Gadhachanda, Venkat Rao,Buchanan, Christine A.,Palzkill, Timothy,Shaw, Robert W.,Spencer, James,Walsh, Timothy R.
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p. 1299 - 1304
(2007/10/03)
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- CONCERNING THE INTERMEDIACY OF MONOCYCLIC β-LACTAMS IN PENICILLIN BIOSYNTHESIS: SYNTHESIS AND ATTEMPTED BIOCONVERSION OF SECO-ISOPENICILLIN N
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The title compound (3a) was synthesized as its dimer by the skeletal rearrangement of protected isopenicillin N-sulfoxide, hydrogenation, hydrolysis of the thiazoline ring, oxidative dimerization and deprotection.The reductive conversion of the dimer to m
- Scott, A. Ian,Shankaranarayan, Ramaswamy,Chung, Sung-Kee
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p. 909 - 927
(2007/10/02)
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- Aminothiazole substituted penicillins and antibacterial compositions thereof
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The present invention provides a compound of formula (I) or a pharmaceutically acceptable salt or in-vivo hydrolysable ester thereof: STR1 wherein R1 is hydrogen or an amino protecting group and R is substituted methyl; optionally substituted C2-12 alkyl, alkenyl or alkynyl; carbocyclyl; aryl or heterocyclyl. These compounds have antibacterial properties, and therefore are of use in the treatment of bacterial infections in humans and animals caused by a wide range of organisms.
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- SYNTHESIS OF 1-(1-D-CARBOXY-2-METHYLPROPYL)-3-L-(5-L-AMONOADIPAMIDO)-4-L-MERCAPTOAZETIDIN-2-ONE (SECO-ISOPENICILLIN N), A POTENTIAL INTERMEDIATE IN PENICILLIN BIOSYNTHESIS.
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The title compound has efficiently been synthesized by the skeletal rearrangement of the protected isopenicillin N sulfoxide and the subsequent hydrolysis of the thiazoline ring.
- Chung, S. K.,Shankaranarayan, R.,Scott, A. I.
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p. 2941 - 2944
(2007/10/02)
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