Synthesis and biological evaluation of zinc chelating compounds as metallo-β-lactamase inhibitors

Kildahl-Andersen, Geir; Schnaars, Christian; Prandina, Anthony; Radix, Sylvie; Borgne, Marc Le; Jordheim, Lars Petter; Gjøen, Tor; Andresen, Adriana Magalhães Santos; Lauksund, Silje; Fröhlich, Christopher; Samuelsen, Ørjan; Rongved, Pål; Åstrand, Ove Alexander Høgmoen

doi:10.1039/c8md00578h

Cited by 14 publications

(11 citation statements)

References 32 publications

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“…TPA is a known lipophilic zinc chelator with high affinity (10 11 M) towards Zn 2+ and has previously been shown to inhibit MBLs (23)(24)(25)(26). Synthesis of ZN148 is achieved through a high-on September 1, 2020 by guest http://aac.asm.org/ Downloaded from yield, 3-step synthesis from commercially available building blocks (Fig.…”

Section: Resultsmentioning

confidence: 99%

ZN148 Is a Modular Synthetic Metallo-β-Lactamase Inhibitor That Reverses Carbapenem Resistance in Gram-Negative Pathogens In Vivo

Samuelsen

Åstrand

Fröhlich

et al. 2020

Antimicrob Agents Chemother

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Carbapenem-resistant Gram-negative pathogens are a critical public health threat and there is an urgent need for new treatments. Carbapenemases (β-lactamases able to inactivate carbapenems) have been identified in both serine β-lactamase (SBL) and metallo-β-lactamase (MBL) families. The recent introduction of SBL carbapenemase inhibitors has provided alternative therapeutic options. Unfortunately, there are no approved inhibitors of MBL-mediated carbapenem-resistance and treatment options for infections caused by MBL-producing Gram-negatives are limited. Here, we present ZN148, a zinc-chelating MBL-inhibitor capable of restoring the bactericidal effect of meropenem and in vitro clinical susceptibility to carbapenems in >98% of a large international collection of MBL-producing clinical Enterobacterales strains (n = 234). Moreover, ZN148 was able to potentiate the effect of meropenem against NDM-1-producing Klebsiella pneumoniae in a murine neutropenic peritonitis model. ZN148 showed no inhibition of the human zinc-containing enzyme glyoxylase II at 500 μM, and no acute toxicity was observed in an in vivo mouse model with cumulative dosages up to 128 mg/kg. Biochemical analysis showed a time-dependent inhibition of MBLs by ZN148 and removal of zinc ions from the active site. Addition of exogenous zinc after ZN148 exposure only restored MBL activity by ∼30%, suggesting an irreversible mechanism of inhibition. Mass-spectrometry and molecular modeling indicated potential oxidation of the active site Cys221 residue. Overall, these results demonstrate the therapeutic potential of a ZN148-carbapenem combination against MBL-producing Gram-negative pathogens and that ZN148 is a highly promising MBL inhibitor that is capable of operating in a functional space not presently filled by any clinically approved compound.

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Section: Resultsmentioning

confidence: 99%

ZN148 Is a Modular Synthetic Metallo-β-Lactamase Inhibitor That Reverses Carbapenem Resistance in Gram-Negative Pathogens In Vivo

Samuelsen

Åstrand

Fröhlich

et al. 2020

Antimicrob Agents Chemother

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“…The NDM-1 enzyme requires Zn 2+ ions for activity. − Overcoming carbapenem resistance by disabling MBLs with Zn 2+ chelators is well-known. ,,− Other strategies overcome resistance by targeting MBLs with inhibitors. ,− Compounds that bind to the LPS layer to facilitate the influx of antibacterial agents are often designed from peptide or peptidomimetic scaffolds, ,,, although resistance has developed . These well-founded and important developments highlight the utility of single-function compounds that inhibit carbapenemases, inhibit efflux pumps, increase the uptake of these inhibitors and various antibiotics, or chelate and sequester Zn 2+ ions essential for MBLs.…”

Section: Resultsmentioning

confidence: 99%

Dual-Function Potentiation by PEG-BPEI Restores Activity of Carbapenems and Penicillins against Carbapenem-Resistant Enterobacteriaceae

et al. 2021

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The rise of life-threatening carbapenem-resistant Enterobacteriaceae (CRE) infections has become a critical medical threat. Some of the most dangerous CRE bacteria can produce enzymes that degrade a wide range of antibiotics, including carbapenems and β-lactams. Infections by CRE have a high mortality rate, and survivors can have severe morbidity from treatment with toxic last-resort antibiotics. CRE have mobile genetic elements that transfer resistance genes to other species. These bacteria also circulate throughout the healthcare system. The mobility and spread of CRE need to be curtailed, but these goals are impeded by having few agents that target a limited range of pathogenic CRE species. Against CRE possessing the metallo-β-lactamase NDM-1, Klebsiella pneumoniae ATCC BAA-2146 and Escherichia coli ATCC BAA-2452, the potentiation of meropenem and imipenem is possible with low-molecular weight branched polyethylenimine (600 Da BPEI) and its poly(ethylene glycol) (PEG)ylated derivative (PEG-BPEI) that has a low in vivo toxicity. The mechanism of action is elucidated with fluorescence assays of drug influx and isothermal calorimetry data showing the chelation of essential Zn2+ ions. These results suggested that 600 Da BPEI and PEG-BPEI may also improve the uptake of antibiotics and β-lactamase inhibitors. Indeed, the CRE E. coli strain is rendered susceptible to the combination of piperacillin and tazobactam. These results expand the possible utility of 600 Da BPEI potentiators, where previously we have demonstrated the ability to improve antibiotic efficacy against antibiotic resistant clinical isolates of Pseudomonas aeruginosa, Staphylococcus aureus, and Staphylococcus epidermidis.

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“…Removal of one 2-methylpyridine group of TPA gives DPA. DPA is a weaker zinc-binder ( K d ~ 10 −8 M) than TPA ( K d ~ 10 −11 M) [ 37 , 46 ], and its inhibition of the five proteases was largely reduced compared to TPA, except for PLN where DPA and TPA were equally effective ( Figure 2 and Figure 3 , Table 1 ). Moderately strong inhibition of DPA was only seen for PLN ( Figure 3 , Table 1 ).…”

Section: Resultsmentioning

confidence: 99%

“…Twenty TPA, DPA, TPEN, pyridine and thiophene derivatives were tested as putative inhibitors of MMP-9, MMP-14, PLN, TLN and ALN. Synthesis of the compounds was reported previously [ 37 , 38 , 39 , 40 ]. The structure of the compounds is shown in Figure 2 and Figure 3 .…”

Section: Methodsmentioning

confidence: 99%

“…Compounds containing metal chelating groups with nitrogen as donor atom may therefore show selectivity for zinc enzymes in front of other metalloenzymes. Derivatives of the zinc chelators di(2-pyridinemethyl)amine (dipicolylamine, DPA) and tri(2-pyridinemethyl)amine (tripicolylamine, TPA) with nitrogen as putative donor atom were found to inhibit metallo-β-lactamases (MBLs) [ 37 , 38 , 39 , 40 ]. MBLs are a group of zinc-dependent hydrolytic enzymes responsible for breaking down β-lactam antibiotics, including carbapenems, penicillins and cephalosporins [ 41 ].…”

Section: Introductionmentioning

confidence: 99%

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Zinc-Chelating Compounds as Inhibitors of Human and Bacterial Zinc Metalloproteases

et al. 2021

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Inhibition of bacterial virulence is believed to be a new treatment option for bacterial infections. In the present study, we tested dipicolylamine (DPA), tripicolylamine (TPA), tris pyridine ethylene diamine (TPED), pyridine and thiophene derivatives as putative inhibitors of the bacterial virulence factors thermolysin (TLN), pseudolysin (PLN) and aureolysin (ALN) and the human zinc metalloproteases, matrix metalloprotease-9 (MMP-9) and matrix metalloprotease-14 (MMP-14). These compounds have nitrogen or sulfur as putative donor atoms for zinc chelation. In general, the compounds showed stronger inhibition of MMP-14 and PLN than of the other enzymes, with Ki values in the lower μM range. Except for DPA, none of the compounds showed significantly stronger inhibition of the virulence factors than of the human zinc metalloproteases. TPA and Zn230 were the only compounds that inhibited all five zinc metalloproteinases with a Ki value in the lower μM range. The thiophene compounds gave weak or no inhibition. Docking indicated that some of the compounds coordinated zinc by one oxygen atom from a hydroxyl or carbonyl group, or by oxygen atoms both from a hydroxyl group and a carbonyl group, and not by pyridine nitrogen as in DPA and TPA.

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Synthesis and biological evaluation of zinc chelating compounds as metallo-β-lactamase inhibitors

Abstract: New MBL inhibitor renders resistant Gram negative bacteria susceptible to carbapenems.

Cited by 14 publications

References 32 publications

ZN148 Is a Modular Synthetic Metallo-β-Lactamase Inhibitor That Reverses Carbapenem Resistance in Gram-Negative Pathogens In Vivo

ZN148 Is a Modular Synthetic Metallo-β-Lactamase Inhibitor That Reverses Carbapenem Resistance in Gram-Negative Pathogens In Vivo

Dual-Function Potentiation by PEG-BPEI Restores Activity of Carbapenems and Penicillins against Carbapenem-Resistant Enterobacteriaceae

Zinc-Chelating Compounds as Inhibitors of Human and Bacterial Zinc Metalloproteases

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