Escherichia coli encoding blaNDM-5 associated with community-acquired urinary tract infections with unusual MIC creep-like phenomenon against imipenem

Gajamer, Varsha Rani; Bhattacharjee, Amitabha; Paul, Deepjyoti; Deshamukhya, Chandrayee; Singh, Ashish; Pradhan, Nilu; Tiwari, Hare Krishna

doi:10.1016/j.jgar.2018.05.004

Cited by 14 publications

(9 citation statements)

References 19 publications

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“…Acquired subclass B1 MBLs are carbapenemases with an exceedingly broad substrate profile and include the most clinically relevant enzymes, such as the VIM‐, NDM‐, and IMP‐types. The global spread of MBL‐producing isolates, not only in the hospital setting but also in the community, makes these enzymes particularly worrying [12,13] …”

Section: Introductionmentioning

confidence: 99%

1,2,4‐Triazole‐3‐Thione Analogues with a 2‐Ethylbenzoic Acid at Position 4 as VIM‐type Metallo‐β‐Lactamase Inhibitors

et al. 2022

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Metallo-β-lactamases (MBLs) are increasingly involved as a major mechanism of resistance to carbapenems in relevant opportunistic Gram-negative pathogens. Unfortunately, clinically efficient MBL inhibitors still represent an unmet medical need. We previously reported several series of compounds based on the 1,2,4-triazole-3-thione scaffold. In particular, Schiff bases formed between diversely 5-substituted-4-amino compounds and 2-carboxybenzaldehyde were broad-spectrum inhibitors of VIM-type, NDM-1 and IMP-1 MBLs. Unfortunately, these compounds were unable to restore antibiotic susceptibility of MBL-producing bacteria, probably because of poor penetration and/or susceptibility to hydrolysis. To improve their microbiological activity, we synthesized and characterized compounds where the hydrazone-like bond of the Schiff base analogues was replaced by a stable ethyl link. This small change resulted in a narrower inhibition spectrum, as all compounds were poorly or not inhibiting NDM-1 and IMP-1, but showed a significantly better activity on VIM-type enzymes, with K i values in the μM to sub-μM range. The resolution of the crystallographic structure of VIM-2 in complex with one of the best inhibitors yielded valuable information about their binding mode. Interestingly, several compounds were shown to restore the β-lactam susceptibility of VIM-type-producing E. coli laboratory strains and also of K. pneumoniae clinical isolates. In addition, selected compounds were found to be devoid of toxicity toward human cancer cells at high concentration, thus showing promising safety.

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Section: Introductionmentioning

confidence: 99%

1,2,4‐Triazole‐3‐Thione Analogues with a 2‐Ethylbenzoic Acid at Position 4 as VIM‐type Metallo‐β‐Lactamase Inhibitors

et al. 2022

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“…MBLs are produced by those Gram-negative bacteria belonging to the WHO first priority list, which are responsible of life-threatening nosocomial infections. In addition, although initially spreading in the hospital setting, MBL-producing isolates are now increasingly causing community-acquired infections [9]. Due to the global dissemination of MBL-producing isolates, these enzymes are major therapeutic targets [10].…”

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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HAL is a multi-disciplinary open access archive for the deposit and dissemination of scientific research documents, whether they are published or not. The documents may come from teaching and research institutions in France or abroad, or from public or private research centers. L'archive ouverte pluridisciplinaire HAL, est destinée au dépôt et à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

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“…Klebsiella pneumoniae, Enterobacter cloacae, Escherichia coli, Pseudomonas aeruginosa, Acinetobacter baumannii). Furthermore, MBL-producing isolates, mainly found in the nosocomial setting, are also increasingly reported in isolates causing community-acquired infections [7]. Due to the global dissemination of carbapenem-resistant MBL-producing isolates, these enzymes are now regarded as major therapeutic targets, despite the discovery.…”

Section: Introductionmentioning

confidence: 99%

4-Amino-1,2,4-triazole-3-thione-derived Schiff bases as metallo-β-lactamase inhibitors

Gavara

Sevaille

Luca

et al. 2020

European Journal of Medicinal Chemistry

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Resistance to β-lactam antibiotics in Gram-negatives producing metallo-β-lactamases (MBLs) represents a major medical threat and there is an extremely urgent need to develop clinically useful inhibitors. We previously reported the original binding mode of 5-substituted-4amino/H-1,2,4-triazole-3-thione compounds in the catalytic site of an MBL. Moreover, we showed that, although moderately potent, they represented a promising basis for the development of broad-spectrum MBL inhibitors. Here, we synthesized and characterized a large number of 4-amino-1,2,4-triazole-3-thione-derived Schiff bases. Compared to the previous series, the presence of an aryl moiety at position 4 afforded an average 10-fold increase in potency. Among 90 synthetic compounds, more than half inhibited at least one of the six tested MBLs (L1, VIM-4, VIM-2, NDM-1, IMP-1, CphA) with Ki values in the µM to sub-µM range. Several were broad-spectrum inhibitors, also inhibiting the most clinically relevant VIM-2 and NDM-1. Active compounds generally contained halogenated, bicyclic aryl or phenolic moieties at position 5, and one substituent among o-benzoic, 2,4-dihydroxyphenyl, pbenzyloxyphenyl or 3-(m-benzoyl)-phenyl at position 4. The crystallographic structure of VIM-2 in complex with an inhibitor showed the expected binding between the triazole-thione moiety and the dinuclear centre and also revealed a network of interactions involving Phe61, Tyr67, Trp87 and the conserved Asn233. Microbiological analysis suggested that the potentiation activity of the compounds was limited by poor outer membrane penetration or efflux. This was supported by the ability of one compound to restore the susceptibility of an NDM-1-producing E. coli clinical strain toward several b-lactams in the presence only of a sub-inhibitory concentration of colistin, a permeabilizing agent. Finally, some compounds were tested against the structurally similar di-zinc human glyoxalase II and found weaker inhibitors of the latter enzyme, thus showing a promising selectivity towards MBLs.

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Escherichia coli encoding blaNDM-5 associated with community-acquired urinary tract infections with unusual MIC creep-like phenomenon against imipenem

Cited by 14 publications

References 19 publications

1,2,4‐Triazole‐3‐Thione Analogues with a 2‐Ethylbenzoic Acid at Position 4 as VIM‐type Metallo‐β‐Lactamase Inhibitors

1,2,4‐Triazole‐3‐Thione Analogues with a 2‐Ethylbenzoic Acid at Position 4 as VIM‐type Metallo‐β‐Lactamase Inhibitors

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

4-Amino-1,2,4-triazole-3-thione-derived Schiff bases as metallo-β-lactamase inhibitors

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