1,2,4-Triazole-3-thione compounds with a 4-ethyl alkyl/aryl sulfide substituent are broad-spectrum metallo-β-lactamase inhibitors with re-sensitization activity

Legru, Alice; Verdirosa, Federica; Hernandez, Jean‐François; Tassone, Giusy; Sannio, Filomena; Benvenuti, Manuela; Conde, Pierre-Alexis; Bossis, Guillaume; Thomas, Charles Swain; Crowder, Michael W.; Dillenberger, Melissa; Becker, Katja; Pozzi, Cecilia; Mangani, Stefano; Docquier, J.D.; Gavara, Laurent

doi:10.1016/j.ejmech.2021.113873

Cited by 18 publications

(38 citation statements)

References 64 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Unfortunately, these compounds were characterized by a narrower inhibition spectrum as they were poorly or not active against NDM‐1 and IMP‐1, possibly accounting for the absence of an aromatic group in the 4‐substituent. This was recently confirmed with a series of compounds substituted at the 4‐position by a thioether‐containing alkyl chain bearing an aryl group at its extremity, which showed a broader spectrum of activity [46] …”

Section: Introductionmentioning

confidence: 71%

“…This was recently confirmed with a series of compounds substituted at the 4-position by a thioether-containing alkyl chain bearing an aryl group at its extremity, which showed a broader spectrum of activity. [46] We herein report on a new series of stable analogues of 1,2,4-triazole-3-thione-based Schiff base inhibitors where the NÀ C double bond was replaced by an ethyl link bearing an obenzoic acid group (Figure 1D). Whereas the compounds showed an inhibition spectrum limited to VIM-type enzymes (as with the 4-alkanoic series), the change to an alkyl link was again found to be significantly beneficial for their antibacterial synergistic activity.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Section: Introductionmentioning

confidence: 71%

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

Self Cite

View full text Add to dashboard Cite

show abstract

“…Additionally, the emergence of metallo-β-lactamases (MBLs) NDM-1 and IMP-4 has also become an established major public health, posing new challenges to the treatment of infectious diseases. MBLs are of great concern due to their carbapenemase activity, their rapid spread in major human opportunistic pathogens, while no clinically useful inhibitor is available yet ( Carcione et al, 2021 ; Legru et al, 2021 ). Avibactam is one of the most important drugs and inhibits β-lactamases of class A, including KPC, class C, and certain class D β-lactamases, mainly OXA-48.…”

Section: Discussionmentioning

confidence: 99%

Coexistence of blaNDM-1 and blaIMP-4 in One Novel Hybrid Plasmid Confers Transferable Carbapenem Resistance in an ST20-K28 Klebsiella pneumoniae

Jia

Zhu

et al. 2022

Front. Microbiol.

View full text Add to dashboard Cite

ObjectivesWe identified a novel hybrid plasmid simultaneously carrying blaNDM-1 and blaIMP-4 in an ST20-K28 carbapenem-resistant Klebsiella pneumoniae (CRKP) strain AZS099 and reported its detailed genetic and phenotypic characterization.MethodsAntimicrobial susceptibility was characterized using broth microdilution method. Complete genome characteristics and plasmid detailed analysis were carried out by PacBio Sequel and Illumina sequencing and further bioinformatics analysis. Conjugation assay, S1-PFGE, Southern blot, plasmid stability, and fitness cost were conducted to the phenotypic characterization of this novel hybrid plasmid.ResultsAZS099 was isolated from a blood specimen obtained from a 3-month baby who presented with biliary tract infection. Susceptibility testing showed that AZS099 was resistant to almost all β-lactams examined, including cephalosporins, combinations of β-lactams and β-lactamase inhibitors, carbapenems, and aztreonam. PacBio and Illumina sequencing together with S1-PFGE and Southern blot showed that blaNDM-1 and blaIMP-4 were simultaneously located on a 296 kb IncFIB(K)/IncHI1B/IncX3 plasmid (pAZS099-NDM-IMP), which consists of four main parts that came from four different types of plasmids. The region harboring blaIMP-4 is located in a class 1 integron designated as In0, which is located in an IS6100-IS26 transposon-like structure with a total length of ~5 kb. The region harboring blaNDM-1 is located in the Tn125 transposon remnant. Conjugation and transformation assay confirmed that the plasmid pAZS099-NDM-IMP has the potential for horizontal transfer and displayed high stability (retention rate > 95%). Furthermore, growth curve assessment confirmed that the presence of pAZS099-NDM-IMP exhibits no growth pressure on bacteria.ConclusionOur research reported a hybrid plasmid coharboring blaNDM-1 and blaIMP-4 in an ST20-K28 CRKP strain. The emergence of novel hybrid plasmid could threaten the control of antimicrobial resistance and should be closely supervised.

show abstract

“…1,2,4-triazole-3-thione (TZT) derivatives: TZT was identified as a potential motif that interacted with the two zinc ions of MBL (L1) through one of the three nitrogen atoms, and sulfur atom, at the same time. An initial crystal structure evaluation of the analogous compound in complex with the L1 enzyme [132] led to synthesis [133][134][135][136][137][138][139][140] (Scheme 36) and enzymatic inhibition studies on a variety of compounds with variable substituents at positions 4 and 5 of TZT. A number of selected compounds exhibited IC 50 values in the micro-molar range against representative MBLs (i.e., L1, VIM-4, VIM-2, NDM-1, and IMP-1 and CphA); however, limited success was observed in the microbiological assays [134][135][136][137]139,140].…”

Section: 24-triazole-3-thione (Tzt) Derivativesmentioning

confidence: 99%

“…An initial crystal structure evaluation of the analogous compound in complex with the L1 enzyme [132] led to synthesis [133][134][135][136][137][138][139][140] (Scheme 36) and enzymatic inhibition studies on a variety of compounds with variable substituents at positions 4 and 5 of TZT. A number of selected compounds exhibited IC 50 values in the micro-molar range against representative MBLs (i.e., L1, VIM-4, VIM-2, NDM-1, and IMP-1 and CphA); however, limited success was observed in the microbiological assays [134][135][136][137]139,140]. In addition to the antimicrobial activity against class B β-lactamases, a series of compounds was assessed in vitro against KPC-2 as well.…”

Section: 24-triazole-3-thione (Tzt) Derivativesmentioning

confidence: 99%

Recent Developments to Cope the Antibacterial Resistance via β-Lactamase Inhibition

et al. 2022

View full text Add to dashboard Cite

Antibacterial resistance towards the β-lactam (BL) drugs is now ubiquitous, and there is a major global health concern associated with the emergence of new β-lactamases (BLAs) as the primary cause of resistance. In addition to the development of new antibacterial drugs, β-lactamase inhibition is an alternative modality that can be implemented to tackle this resistance channel. This strategy has successfully revitalized the efficacy of a number of otherwise obsolete BLs since the discovery of the first β-lactamase inhibitor (BLI), clavulanic acid. Over the years, β-lactamase inhibition research has grown, leading to the introduction of new synthetic inhibitors, and a few are currently in clinical trials. Of note, the 1, 6-diazabicyclo [3,2,1]octan-7-one (DBO) scaffold gained the attention of researchers around the world, which finally culminated in the approval of two BLIs, avibactam and relebactam, which can successfully inhibit Ambler class A, C, and D β-lactamases. Boronic acids have shown promise in coping with Ambler class B β-lactamases in recent research, in addition to classes A, C, and D with the clinical use of vaborbactam. This review focuses on the further developments in the synthetic strategies using DBO as well as boronic acid derivatives. In addition, various other potential serine- and metallo- β-lactamases inhibitors that have been developed in last few years are discussed briefly as well. Furthermore, binding interactions of the representative inhibitors have been discussed based on the crystal structure data of inhibitor-enzyme complex, published in the literature.

show abstract

1,2,4-Triazole-3-thione compounds with a 4-ethyl alkyl/aryl sulfide substituent are broad-spectrum metallo-β-lactamase inhibitors with re-sensitization activity

Cited by 18 publications

References 64 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

Coexistence of blaNDM-1 and blaIMP-4 in One Novel Hybrid Plasmid Confers Transferable Carbapenem Resistance in an ST20-K28 Klebsiella pneumoniae

Recent Developments to Cope the Antibacterial Resistance via β-Lactamase Inhibition

Contact Info

Product

Resources

About