Structure-activity relationship study and optimisation of 2-aminopyrrole-1-benzyl-4,5-diphenyl-1H-pyrrole-3-carbonitrile as a broad spectrum metallo-β-lactamase inhibitor (original) (raw)
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Novel imidazole substituted 6-methylidene-penems as broad-spectrum β-lactamase inhibitors
Bioorganic & Medicinal Chemistry, 2004
b-Lactamases are serine and metallo-dependent enzymes produced by the bacteria in defense against b-lactam antibiotics. Production of class-A, class-B, and class-C enzymes by the bacteria make the use of b-lactam antibiotics ineffective in certain cases. To overcome resistance to b-lactam antibiotics, several b-lactamase inhibitors such as clavulanic acid, sulbactam, and tazobactam are widely used in the clinic in combination with b-lactam antibiotics. However, single point mutations within these enzymes have allowed bacteria to overcome the inhibitory effect of the commercially approved b-lactamase inhibitors. Although the commercially available b-lactamase inhibitor/b-lactam antibiotic combinations are effective against class-A producing bacteria and many extended spectrum b-lactamase (ESBLÕs) producing bacteria they are less effective against class-C enzymes expressing bacteria. To circumvent this problem, based on modeling studies several novel imidazole substituted 6-methylidene-penem derivatives were synthesized and tested against various b-lactamase producing isolates. The present paper deals with the synthesis and structure-activity relationships (SAR) of these compounds.
Inhibition of metallo-β-lactamases by pyridine monothiocarboxylic acid analogs
The Journal of Antibiotics, 2010
Metallo-b-lactamases (MBLs) are potent bacterial enzymes that can destroy almost all classes of b-lactams, including carbapenems. Strong hydrolytic activity against carbapenems is observed when these enzymes are produced chromosomally by clinically important pathogens such as Stenotrophomonas maltophilia and Bacteroides fragilis. 1-3 More importantly, many MBLs now appear as plasmid-encoded enzymes that can be transferred among the Enterobacteriaceae as well as the non-fermentors. 2,3 Over 80 unique MBLs have been described in the literature, with at least 23 members in each of the inosine monophosphate and VIM families of plasmid-encoded MBLs. 1 Although genes encoding these metalloenzymes may be found in the bacterial chromosome, they are not always expressed in B. fragilis. 4,5 The MBL genes encoded on mobile bacterial plasmids in Pseudomonas aeruginosa, 6 Serratia marcescens 7 and many other Gram-negative pathogens are also found with genes encoding other types of antibiotic resistance (for example, aminoglycosides), 3 resulting in multidrug-resistant pathogens of high clinical importance. Consequently, clinical failures of carbapenems as a result of MBLs continue to be a serious problem. For this reason, an inhibitor of MBLs could provide a distinct advantage when used in combination therapy with susceptible b-lactam antibiotics. MBLs require an active site divalent zinc cation to hydrolyze the amide bond in the b-lactam ring of susceptible compounds. These enzymes are inactivated by chelating agents such as EDTA, 1,10-ophenanthroline and dipicolinic acid (1, Figure 1), 8 but not by classical b-lactamase inhibitors such as clavulanic acid. Payne et al. 9 reported that MBLs were irreversibly inhibited by mercaptoacetic acid thiol ester derivatives by a mechanism based on the delivery of mercaptoacetic acid, forming a disulfide linkage with the active site serine. Conversely, mercaptophenylacetic acid thiol ester derivatives act as competitive inhibitors of the enzyme. 10 Using an automated screen, 19 366 natural product extracts were tested for time-dependent inhibitory activity against the CcrA MBL from B. fragilis. Potent activity was identified from actinomycete
Novel imidazole substituted 6-methylidene-penems as broad-spectrum �-lactamase inhibitors
Bioorgan Med Chem, 2004
β-Lactamases are serine and metallo-dependent enzymes produced by the bacteria in defense against β-lactam antibiotics. Production of class-A, class-B, and class-C enzymes by the bacteria make the use of β-lactam antibiotics ineffective in certain cases. To overcome resistance to β-lactam antibiotics, several β-lactamase inhibitors such as clavulanic acid, sulbactam, and tazobactam are widely used in the clinic in combination with β-lactam antibiotics. However, single point mutations within these enzymes have allowed bacteria to overcome the inhibitory effect of the commercially approved β-lactamase inhibitors. Although the commercially available β-lactamase inhibitor/β-lactam antibiotic combinations are effective against class-A producing bacteria and many extended spectrum β-lactamase (ESBL’s) producing bacteria they are less effective against class-C enzymes expressing bacteria. To circumvent this problem, based on modeling studies several novel imidazole substituted 6-methylidene-penem derivatives were synthesized and tested against various β-lactamase producing isolates. The present paper deals with the synthesis and structure–activity relationships (SAR) of these compounds.A series of novel imidazole substituted 6-methylidene-penems has been synthesized (R = heterocycle) and was shown to be potent, broad-spectrum β-lactamase inhibitors against class-A and class-C enzymes. The present paper deals with the design, synthesis, and structure–activity relationships (SAR) of compounds 11–15.
Captopril analogues as metallo-β-lactamase inhibitors
Bioorganic & Medicinal Chemistry Letters, 2016
A number of captopril analogues were synthesised and tested as inhibitors of the metallo--lactamase IMP-1. Structure-activity studies showed that the methyl group was unimportant for activity, and that the potencies of these inhibitors could be best improved by shortening the length of the mercaptoalkanoyl side-chain. Replacing the thiol group with a carboxylic acid led to complete loss of activity, and extending the length of the carboxylate group led to decreased potency. Good activity could be maintained by substituting the proline ring with pipecolic acid.
Polypyridine ligands as potential metallo-β-lactamase inhibitors
Journal of Inorganic Biochemistry
Bacteria have developed multiple resistance mechanisms against the most used antibiotics. In particular, zinc-dependent metallo-β-lactamase producing bacteria are a growing threat, and therapeutic options are limited. Zinc chelators have recently been investigated as metallo-β-lactamase inhibitors, as they are often able to restore carbapenem susceptibility. We synthesized polypyridyl ligands, N,N'-bis(2-pyridylmethyl)-ethylenediamine, N,N,N'-tris(2-pyridylmethyl)-ethylenediamine, N,N'-bis(2-pyridylmethyl)-ethylenediamine-N-acetic acid (N,N,N'-tris(2-pyridylmethyl)-ethylenediamine-N'-acetic acid, which can form zinc(II) complexes. We tested their ability to restore the antibiotic activity of meropenem against three clinical strains isolated from blood and metallo-β-lactamase producers (Klebsiella pneumoniae, Enterobacter cloacae, and Stenotrophomonas maltophilia). We functionalized N,N,N'-tris(2-pyridylmethyl)-ethylenediamine with D-alanyl-D-alanyl-D-alanine methyl ester with the aim to increase bacterial uptake. We observed synergistic activity of four polypyridyl ligands with meropenem against all tested isolates, while the combination N,N'-bis(2-pyridylmethyl)-ethylenediamine and meropenem was synergistic only against New Delhi and Verona integron-encoded metallo-β-lactamase-producing bacteria. All synergistic interactions restored the antimicrobial activity of meropenem, providing a significant decrease of minimal inhibitory concentration value (by 8- to 128-fold). We also studied toxicity of the ligands in two normal peripheral blood lymphocytes.
An Update on the Status of Potent Inhibitors of Metallo-β-Lactamases.
The production of metallo-β-lactamases is the most important strategy by which pathogenic bacteria become resistant to currently known β-lactam antibiotics. The emergence of these enzymes is particularly concerning for the future treatment of bacterial infections. There are no clinically available drugs capable of inhibiting any of the metallo-β-lactamases, so there is an urgent need to find such inhibitors. In this review, an up-to-date status of the inhibitors investigated for the inhibition of metallo-β-lactamases has been given so that this rich source of structural information of presently known metallo-β-lactamases could be helpful in generating a broad-spectrum potent inhibitor of metallo-β-lactamases.
Biomolecules
To fight the increasingly worrying bacterial resistance to antibiotics, the discovery and development of new therapeutics is urgently needed. Here, we report on a new series of 1,2,4-triazole-3-thione compounds as inhibitors of metallo-β-lactamases (MBLs), which represent major resistance determinants to β-lactams, and especially carbapenems, in Gram-negative bacteria. These molecules are stable analogs of 4-amino-1,2,4-triazole-derived Schiff bases, where the hydrazone-like bond has been reduced (hydrazine series) or the 4-amino group has been acylated (hydrazide series); the synthesis and physicochemical properties thereof are described. The inhibitory potency was determined on the most clinically relevant acquired MBLs (IMP-, VIM-, and NDM-types subclass B1 MBLs). When compared with the previously reported hydrazone series, hydrazine but not hydrazide analogs showed similarly potent inhibitory activity on VIM-type enzymes, especially VIM-2 and VIM-4, with Ki values in the micromo...
The in vitro inhibitory activity of polypyridine ligands towards subclass B1 metallo-β-lactamases
Results in chemistry, 2023
Antimicrobial resistance leads to the ineffectiveness of antimicrobials, hampering the ability to cure infections. Zinc-dependent metallo ß-lactamases (MBLs) producing bacteria represent a threat to public health due to limited therapeutic options. Zinc chelators are able to inhibit MBLs and have the potential to restore carbapenem susceptibility. Recently, polypyridine ligands named Bispicen (N,N'-Bis(2-pyridymethyl)-ethylenediamine), Trispicen (N,N,N'-Tris(2-pyridylmethyl)-ethylenediamine), TrispicenA (N,N,N'-tris([2-pyridylmethyl)-ethylenediamine-N'-acetic acid) and TrispicenDALA (N,N,N'-tris([2-pyridylmethyl)-ethylenediamine-N'-acetyl-Dalanyl-D-alanyl-D-alanine methyl ester) were evaluated for their ability to interfere with the Zn-ion network by interactions in the binding site of MBLs. We report on the inhibitory activity of these ligands towards three subclass B1 MBLs (NDM-1, VIM-1 and IMP-1) by kinetic analysis, demonstrating that all compounds, except TrispicenDALA, acted as competitive inhibitors towards NDM-1 and VIM-1. Bispicen was more active against VIM-1 with K i value of 0.13 μM while NDM-1 was highly inhibited by Trispicen with K i value of 0.08 μM. The IMP-1 enzyme was resistant to these compounds showing K i and IC 50 values higher than 500 μM. Docking study reveals that all compounds interact with residues of the MBL active site mainly by the formation of piinteractions and chelation of both Zn ions. Polypyridine ligands deserve attention for their inhibitory potential towards NDM-1 and VIM-1.
Antimicrobial Agents and Chemotherapy, 2002
This work describes the discovery and characterization of a novel series of tricyclic natural product-derived metallo--lactamase inhibitors. Natural product screening of the Bacillus cereus II enzyme identified an extract from a strain of Chaetomium funicola with inhibitory activity against metallo--lactamases. SB236050, SB238569, and SB236049 were successfully extracted and purified from this extract. The most active of these compounds was SB238569, which possessed K i values of 79, 17, and 3.4 M for the Bacillus cereus II, Pseudomonas aeruginosa IMP-1, and Bacteroides fragilis CfiA metallo--lactamases, respectively, yet none of the compounds exhibited any inhibitory activity against the Stenotrophomonas maltophilia L-1 metallo--lactamase (50% inhibitory concentration > 1,000 M). The lack of activity against angiotensin-converting enzyme and serine -lactamases demonstrated the selective nature of these compounds. The crystal structure of SB236050 complexed in the active site of CfiA has been obtained to a resolution of 2.5 Å. SB236050 exhibits key polar interactions with Lys184, Asn193, and His162 and a stacking interaction with the indole ring of Trp49 in the flap, which is in the closed conformation over the active site groove. SB236050 and SB238569 also demonstrate good antibacterial synergy with meropenem. Eight micrograms of SB236050 per ml gave rise to an eightfold drop in the MIC of meropenem for two clinical isolates of B. fragilis producing CfiA, making these strains sensitive to meropenem (MIC < 4 g/ml). Consequently, this series of metallo--lactamase inhibitors exhibit the most promising antibacterial synergy activity so far observed against organisms producing metallo--lactamases.