New Carbapenemase Inhibitors: Clearing the Way for the β-Lactams

Vázquez-Ucha, Juan Carlos; Arca-Suárez, Jorge; Bou, Germán; Beceiro, Alejandro

doi:10.3390/ijms21239308

Cited by 90 publications

(91 citation statements)

References 164 publications

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“…However, they only target some serine-b-lactamases (SBLs) [12]. Two MBL inhibitors are under clinical development (phase III trials for taniborbactam, phase I for QPX7728) [13][14][15][16], and only few other compounds are promising [17][18][19]. In fact, one major difficulty is the existence of numerous MBLs showing subtle differences in their active sites and the discovery of a broad-spectrum inhibitor is a true challenge [12,20,21].…”

Section: Introductionmentioning

confidence: 99%

4-Alkyl-1,2,4-triazole-3-thione analogues as metallo-β-lactamase inhibitors

Gavara

Legru

Verdirosa

et al. 2021

Bioorganic Chemistry

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Section: Introductionmentioning

confidence: 99%

4-Alkyl-1,2,4-triazole-3-thione analogues as metallo-β-lactamase inhibitors

Gavara

Legru

Verdirosa

et al. 2021

Bioorganic Chemistry

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“…In our search, in the case of P. aeruginosa isolates, an important role could be played by impermeability (porin loss), production of PDC variants, OXA enzymes (other than OXA-48) or hyperexpression of efflux systems. In particular, it is well-known that AVI may show a potent inhibitory activity against the basal AmpC produced by P. aeruginosa , even though extended-spectrum OXA enzymes can escape its wide spectrum of activity [ 71 ]. Selection of extended-spectrum OXA-2 or OXA-10 variants such as OXA-539, OXA-681 and OXA-14 has previously been associated with in vivo acquisition of high-level CZA resistance [ 72 , 73 , 74 ], while OXA-10 and OXA-18 enzymes have been associated with ATM’s high MIC values [ 75 ].…”

Section: Discussionmentioning

confidence: 99%

The Revival of Aztreonam in Combination with Avibactam against Metallo-β-Lactamase-Producing Gram-Negatives: A Systematic Review of In Vitro Studies and Clinical Cases

et al. 2021

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Infections caused by metallo-β-lactamase (MBL)-producing Enterobacterales and Pseudomonas are increasingly reported worldwide and are usually associated with high mortality rates (>30%). Neither standard therapy nor consensus for the management of these infections exist. Aztreonam, an old β-lactam antibiotic, is not hydrolyzed by MBLs. However, since many MBL-producing strains co-produce enzymes that could hydrolyze aztreonam (e.g., AmpC, ESBL), a robust β-lactamase inhibitor such as avibactam could be given as a partner drug. We performed a systematic review including 35 in vitro and 18 in vivo studies on the combination aztreonam + avibactam for infections sustained by MBL-producing Gram-negatives. In vitro data on 2209 Gram-negatives were available, showing the high antimicrobial activity of aztreonam (MIC ≤ 4 mg/L when combined with avibactam) in 80% of MBL-producing Enterobacterales, 85% of Stenotrophomonas and 6% of MBL-producing Pseudomonas. Clinical data were available for 94 patients: 83% of them had bloodstream infections. Clinical resolution within 30 days was reported in 80% of infected patients. Analyzing only patients with bloodstream infections (64 patients), death occurred in 19% of patients treated with aztreonam + ceftazidime/avibactam. The combination aztreonam + avibactam appears to be a promising option against MBL-producing bacteria (especially Enterobacterales, much less for Pseudomonas) while waiting for new antimicrobials.

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“…VNRX-7145 is a novel cyclic boronate β-lactamase inhibitor with potent inhibitory activity against class A, C, and D β-lactamases [ 67 ]. In vivo, VNRX-7145 undergoes biotransformation to an active inhibitor, VNRX-5236 [ 68 ]. It is being developed in combination with ceftibuten as an oral therapy by VenatoRx Pharmaceuticals, Inc. (Pennsylvania, USA).…”

Section: Novel β-Lactam and β-Lactamase Inhibitorsmentioning

confidence: 99%

Oral Antibiotics in Clinical Development for Community-Acquired Urinary Tract Infections

2021

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The treatment of urinary tract infections (UTIs) has been complicated by the emergence of multidrug-resistant, b-lactamase-expressing pathogens. As a result of the limited treatment options, patients often require hospitalization and intravenous therapy. In essence, a strong unmet need for oral antibiotics, active against extended-spectrum b-lactamase (ESBL) uropathogens has emerged. Oral carbapenems (tebipenem and sulopenem) and oral cephalosporin/b-lactamase inhibitor combinations are in various stages of clinical development for the treatment of uncomplicated and complicated UTI. Tebipenem, if approved, will be the first oral treatment for complicated UTI while sulopenem will be for uncomplicated UTI. The b-lactamase inhibitors ETX0282, VNRX7145, ARX1796, and QPX7728 are combined with cefpodoxime proxetil or ceftibuten that achieve favorable exposures in urine compared to other uropathogen-active oral cephalosporins.The combination ceftibuten-QPX7728 has potential broad-spectrum coverage against carbapenemase producers including metallo b-lactamase producers. Other novel combinations, namely cefpodoxime/ETX0282, ceftibuten/VNRX-7145, and ceftibuten/ ARX1796, have also demonstrated excellent activity against Klebsiella pneumoniae carbapanemase (KPC) and OXA-48-like producers. All these agents, upon their arrival for commercial use, would strengthen the outpatient therapy.

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New Carbapenemase Inhibitors: Clearing the Way for the β-Lactams

Cited by 90 publications

References 164 publications

4-Alkyl-1,2,4-triazole-3-thione analogues as metallo-β-lactamase inhibitors

4-Alkyl-1,2,4-triazole-3-thione analogues as metallo-β-lactamase inhibitors

The Revival of Aztreonam in Combination with Avibactam against Metallo-β-Lactamase-Producing Gram-Negatives: A Systematic Review of In Vitro Studies and Clinical Cases

Oral Antibiotics in Clinical Development for Community-Acquired Urinary Tract Infections

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