6-Arylmethylidene Penicillin-Based Sulfone Inhibitors for Repurposing Antibiotic Efficiency in Priority Pathogens

Rodríguez, Diana Catalina; Maneiro, María; Vázquez-Ucha, Juan Carlos; Beceiro, Alejandro; González‐Bello, Concepción

doi:10.1021/acs.jmedchem.0c00127

Cited by 16 publications

(28 citation statements)

References 49 publications

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“…The effectiveness of β-lactamases is reduced by enzyme inhibitors and these are often co-administered with β-lactam antibiotics, increasing antibiotic efficacy. β-lactamase inhibitors used in treating P. aeruginosa infections include clavulanate, tazobactam, avibactam, and vaborbactam for Class A β-lactamases, relebactam for Class A and Class C enzymes, and avibactam for class C and a limited number of class D β-lactamases [217][218][219][220][221]. Class B enzymes can be inhibited by metal ion chelators, but currently, these are not in clinical use as β-lactamase inhibitors [217,222].…”

Section: Degradation Of β-Lactams By β-Lactamasesmentioning

confidence: 99%

β-lactam Resistance in Pseudomonas aeruginosa: Current Status, Future Prospects

Glen

Lamont

2021

Pathogens

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Pseudomonas aeruginosa is a major opportunistic pathogen, causing a wide range of acute and chronic infections. β-lactam antibiotics including penicillins, carbapenems, monobactams, and cephalosporins play a key role in the treatment of P. aeruginosa infections. However, a significant number of isolates of these bacteria are resistant to β-lactams, complicating treatment of infections and leading to worse outcomes for patients. In this review, we summarize studies demonstrating the health and economic impacts associated with β-lactam-resistant P. aeruginosa. We then describe how β-lactams bind to and inhibit P. aeruginosa penicillin-binding proteins that are required for synthesis and remodelling of peptidoglycan. Resistance to β-lactams is multifactorial and can involve changes to a key target protein, penicillin-binding protein 3, that is essential for cell division; reduced uptake or increased efflux of β-lactams; degradation of β-lactam antibiotics by increased expression or altered substrate specificity of an AmpC β-lactamase, or by the acquisition of β-lactamases through horizontal gene transfer; and changes to biofilm formation and metabolism. The current understanding of these mechanisms is discussed. Lastly, important knowledge gaps are identified, and possible strategies for enhancing the effectiveness of β-lactam antibiotics in treating P. aeruginosa infections are considered.

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Section: Degradation Of β-Lactams By β-Lactamasesmentioning

confidence: 99%

β-lactam Resistance in Pseudomonas aeruginosa: Current Status, Future Prospects

Glen

Lamont

2021

Pathogens

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“…Compound SA-1-204 ( 1b ) inhibits class A and class D β-lactamases efficiently, and LN-1-255 ( 1c ) combined with piperacillin was found to be more active against Escherichia coli -DH10B strains containing extended spectrum and inhibitor-resistant β-lactamases than the clinically used combination of piperacillin and tazobactam . The mechanism of action of these β-lactamase inhibitors was elucidated by crystallographic and spectroscopic studies. − Very recently, derivatives of LN-1-255 ( 1c ) that are substituted at the pyridine ring were synthesized and successfully tested against multidrug-resistant Acinetobacter baumannii in combination with the β-lactam antibiotic imipenem . Biological activities of arylidene-β-lactams are, however, not limited to β-lactamase inhibition: several compounds with this structural pattern (e.g., 1e ) are active against the fungal plant pathogen Alternaria solani Sorauer, the causal agent of early blight.…”

Section: Introductionmentioning

confidence: 99%

“…Previously reported syntheses of arylidene-β-lactams 1 , as for example the β-lactamase inhibitors SA-1-204 ( 1b ) or LN-1-255 ( 1c ), rely on a Wittig olefination of 6-oxo-penicillanic acid derivatives, which were in turn synthesized from 6-aminopenicillanic acid in a multistep synthesis . Alternative strategies (as for example used for the synthesis of 1e ) proceed via a late-stage β-lactamization of 2-aminomethyl cinnamates, which are accessible via a sequence of Baylis-Hillman reaction, dehydrative bromination, and nucleophilic substitution. ,, …”

Section: Introductionmentioning

confidence: 99%

“…10−12 Very recently, derivatives of LN-1-255 (1c) that are substituted at the pyridine ring were synthesized and successfully tested against multidrug-resistant Acinetobacter baumannii in combination with the β-lactam antibiotic imipenem. 13 Biological activities of arylidene-β-lactams are, however, not limited to β-lactamase inhibition: several compounds with this structural pattern (e.g., 1e) are active against the fungal plant pathogen Alternaria solani Sorauer, the causal agent of early blight. This disease mainly affects potato and tomato plants and is responsible for severe economic losses.…”

Section: ■ Introductionmentioning

confidence: 99%

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Synthesis of Arylidene-β-lactams via exo-Selective Matsuda-Heck Arylation of Methylene-β-lactams

Riemer

Krüger

et al. 2021

J. Org. Chem.

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exo-Methylene-β-lactams were synthesized in two steps from commercially available 3-bromo-2-(bromomethyl)propionic acid and reacted with arene diazonium salts in a Heck-type arylation in the presence of catalytic amounts of Pd(OAc) 2 under ligand-free conditions. The products, arylidene-βlactams, were obtained in high yields as single isomers. The βhydride elimination step of the Pd-catalyzed coupling reaction proceeds with high exo-regioselectivity and E-stereoselectivity. With aryl iodides, triflates, or bromides, the coupling products were isolated only in low yields, due to extensive decomposition of the starting material at elevated temperatures. This underlines that arene diazonium salts can be superior arylating reagents in Hecktype reactions and yield coupling products in synthetically useful yields and selectivities when conventional conditions fail.

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“…In this regard, the emergence of new broad-spectrum inhibitors, mainly durlobactam (formerly ETX2514), a 1,6-diazabicyclo[3.2.1]octane [18]; QPX7728, a cyclic boronate [19]; and LN-1-255, a penicillin sulfone derivative (all of which are able to block the most widespread CHDLs produced by A. baumannii) may represent a step forward in the fight against infections caused by β-lactam-resistant and, in particular, carbapenem-resistant A. baumannii. LN-1-255 is a 6-alkylidene-2′-substituted penicillin sulfone inhibitor with demonstrated activity against class A, class C, and class D β-lactamases [20,21] and against the carbapenem-hydrolyzing oxacillinases produced by A. baumannii. This inhibitor presents a catechol moiety responsible for effective internalization via bacterial iron uptake pathways.…”

Section: Introductionmentioning

confidence: 99%

Activity of Imipenem, Meropenem, Cefepime, and Sulbactam in Combination with the β-Lactamase Inhibitor LN-1-255 against Acinetobacter spp.

et al. 2021

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Treatment of infections caused by Acinetobacter spp., particularly A. baumannii, is a major clinical problem due to its high rates of antibiotic resistance. New strategies must be developed; therefore, restoration of β-lactam efficacy through the use of β-lactamase inhibitors is paramount. Activities of the antibiotics imipenem, meropenem, cefepime, and sulbactam in combination with the penicillin-sulfone inhibitor LN-1-255 were tested by microdilution against 148 isolates of Acinetobacter spp. collected in 14 hospitals in Spain in 2020. Relevantly, the MIC90 (i.e., minimum concentration at which 90% of isolates were inhibited) of antibiotics in combination with LN-1-255 decreased 4- to 8-fold for all of the Acinetobacter isolates. Considering only the carbapenem-resistant A. baumannii isolates, which produce carbapenem-hydrolyzing class D β-lactamases, the addition of LN-1-255 decreased the resistance rates from 95.1% to 0% for imipenem, from 100% to 9.8% for meropenem, from 70.7% to 7.3% for cefepime, and sulbactam resistance rates from 9.8% to 0% and intermediate susceptibility rates from 53.7% to 2.4%. The inhibitor also decreased the minimum inhibitory concentrations (MICs) when tested against non-carbapenem-resistant Acinetobacter spp. isolates. In conclusion, combining LN-1-255 with imipenem, meropenem, cefepime, and sulbactam to target A. baumannii, and especially carbapenem-resistant isolates, represents an attractive option that should be developed for the treatment of infections caused by this pathogen.

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6-Arylmethylidene Penicillin-Based Sulfone Inhibitors for Repurposing Antibiotic Efficiency in Priority Pathogens

Cited by 16 publications

References 49 publications

β-lactam Resistance in Pseudomonas aeruginosa: Current Status, Future Prospects

β-lactam Resistance in Pseudomonas aeruginosa: Current Status, Future Prospects

Synthesis of Arylidene-β-lactams via exo-Selective Matsuda-Heck Arylation of Methylene-β-lactams

Activity of Imipenem, Meropenem, Cefepime, and Sulbactam in Combination with the β-Lactamase Inhibitor LN-1-255 against Acinetobacter spp.

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