TABLE 4

Types and characteristics of known metallo-β-lactamase inhibitors

Metallo-β-lactamase inhibitor(s)SourceKi (μM)IC50 (μM)Type of inhibitionReference(s)
B1B2B3B1B2B3
Carboxylates, tetrazoles, and hydroxamates
    Maleic acidsSynthetic0.4–120a2.5–13Competitive67, 68
    Succinic acidSynthetic3.30.0027–49015–300Irreversible162, 163, 164
    Phthalic acidSynthetic0.2–24369, 70, 165
    N-AcylhydrazonesSynthetic1.02–24166
    2-Substituted 4,5-dihydrothiazole-4-carboxylic acidSynthetic3.3–5.15–7773
    3-Mercapto-1,2,4-triazoles and N-acylated thiosemicarbazidesSynthetic11–75Mixed167
    N-Heterocyclic dicarboxylic acid derivativesSynthetic0.6–63.5–7.10.7–2Mixed168
    Biphenyl tetrazolesSynthetic0.6–1.60.3–860Competitive49, 169
    Hydroxamates (amino acid derived)Synthetic6.1–18Competitive50, 170
Phenazines
    SB 212021Streptomyces3719Reversible171
    SB212305Streptomyces751Reversible171
Trifluoromethyl ketones and alcoholsSynthetic30–1,0006–2171.5–5,000Irreversible for subclass B2172
    Trifluoromethyl ketone 5b (3S)Synthetic500615Irreversible for subclass B2172
    Trifluoromethyl ketone 5′a (3R)Synthetic700113Irreversible for subclass B2172
    Trifluoromethyl ketone 5a (3S)Synthetic300441.5Irreversible for subclass B2172
    Trifluoromethyl alcohol 4′b (2R, 3R), (2S, 3R)Synthetic3020>5,000Irreversible for subclass B2172
    Trifluoromethyl alcohol 4b (2R, 3S), (2S, 3S)Synthetic1,00019>5,000Irreversible for subclass B2172
    Trifluoromethyl alcohol 4′a (2R, 2R), (2S, 3R)Synthetic70021735Irreversible for subclass B2172
β-Lactam analogues
    1β-MethylcarbapenemSynthetic0.0037–0.81<0.1–>10Reversible79
    Penicillin-derived inhibitorsSynthetic1.4–>2000.1–>20052
    Thioxo-cephalosporin derivativesSynthetic29–720Competitive81, 173
    Cyclobutanone analogues of β-lactamsSynthetic122–1,000Reversible83
    β-Lactam substratesSynthetic2,300Irreversible174, 175
Peptides
    Cys-Val-His-Ser-Pro-Asn-Arg-Glu-CysSynthetic16/9Mixed176
    Homocysteinyl peptideSynthetic0.0021–1Reversible competitive177
    Cysteinyl peptideSynthetic3.0–1,0000.9–3.7Reversible55
Pyridine dicarboxylates
    2-Picolinic acidSynthetic54–955.729–62Competitive54
    Pyridine-2,4-dicarboxylic acidSynthetic78–984.565–78Competitive54
    Pyridine monothiocarboxylic acid analoguesNatural products0.14–2500.6–340Reversible86
Natural products
    Flavonoids: galangin, quercetinPlants18.5–185Irreversible76
    Tricyclic natural products: SB238569, SB236050, SB 236049Chaetomium fanicola17–883.4–150.7–2562–29>1,000Competitive56
    PolyketidesPenicillium sp.88–9577
Triazoles and N-acylated thiosemicarbazides
    SulfonyltriazoleSynthetic0.41–1.43.3–>56Competitive178
    NH-1,2,3-triazole inhibitorsSynthetic0.01–0.20.07–21Competitive and mixed179
    4-Methyl-5-(trifluoromethyl)-4H-1,2,4-triazole-3-thiolSynthetic970Competitive180
    3-Mercapto-1,2,4-triazoles and N-acylated thiosemicarbazidesSynthetic11–75Mixed167
Pyrrole derivatives
    Pyrrole-based inhibitorsSynthetic12–33Competitive53
    Tetrahydropyrimidine-2-thione and pyrrole derivativesSynthetic19–235Competitive75
Nucleic acids
    Single-stranded DNAsDNA0.00031–0.00920.15–0.8Reversible and noncompetitive57, 181
    Double-stranded DNAsDNA0.1–0.1030.01–0.02Reversible57
    DNA nanoribbonDNA3.3–4011.75.7Nonintercalative binding182
Sulfonic acid derivatives
    Bulcegin AMicroorganisms2302.5Competitive183
    4-Morpholinoethanesulfonic acidSynthesis23,000Competitive51
    N-Arylsulfonyl hydrazonesSynthesis0.7–6.61.6–150Reversible competitive184
Metal chelators
    Ca-EDTASynthesis28Noncompetitive73
    Aspergilomarasamine AAspergillus versicolor4–11Irreversible78, 185
    NOTA, DOTA, TPEN, DPA, NODAGASynthetic
    Dipicolinic acidSynthetic5.70.14–2500.6–340Competitive54, 86
    o-PhenanthrolineSynthetic55Reversible
Thioester and thiol derivatives
    ThiodepsipeptidesSynthetic0.25–24059
    Thioesters and thiolsSynthetic0.01–40.0004–740Reversible competitive59, 186, 187
    Mercaptoacetic acid derivativesSynthetic428–6450.55–302–186Irreversible61, 188
    Mercaptophenylacetic acid derivativesSynthetic0.02–1,5001440.3–0.622–4791.95–8Reversible competitive189
    MercaptocarboxylateSynthetic1.1–16.4190
    Mercaptophosphonate derivativesSynthetic1–160.3–240.4–40Competitive191
    1β-MethylcarbapenamensSynthetic0.004–0.81>0.1–979
    d-CaptropilSynthetic0.5–7002.7–720.072–261.8Competitive64, 74, 192
    l-CaptoprilSynthetic1.5–6519–9504.4–157.4Competitive64, 74, 193
    (R)-Thiomandelic acidSynthetic0.03–0.81440.3–0.6Reversible62, 194
    Various charged and neutral thiolsSynthetic1.3–200Slow-binding reversible195
    Dansyl-derived thiolsSynthetic0.14–1.30.7–6.3196
    Penicillin-derived thiolsSynthetic1.4–1060.1–7252, 80
    Bisthiazolidines derivativesSynthetic3–840.3–291,041Competitive197
  • a —, no data found.