Principal kinetic parameters associated with inhibition of TEM-1 and P99 β-lactamases by NXL104, TZB, and CLA as derived from the kobs valuesa

EnzymeInactivatorPRbk2 (s−1)(ki)lim (s−1)K (μM)cKm (μM)ck2/K (M−1 s−1)(ki)lim/Km (M−1 s−1)
TEM-1NXL1040.110.3 (0.26)370,000
TEM-1TZB>1500.020.014d (0.030)1,400,000
TEM-1CLA>1000.030.5e (0.8)60,000
P99NXL1040.055.1 (7.7)10,000
P99TZB110.15300 (170)500
  • a Standard deviation of <20% for all the values except as noted.

  • b PR, partition ratio. This ratio does not apply (—) to a simple linear scheme where stability of the EI complex results from a k3 value that is close to zero. If a rearrangement does in fact take place with NXL104 (rate constant k4), then the k3/k4 ratio values for both P99 and TEM-1 would be close to zero according to the data shown in Fig. 3a and c. NXL104 obeys scheme 1 with k3 = 0 (or close to) for both enzymes; TZB and CLA obey the branched-pathway model.

  • c The value in parentheses is the Ki value obtained by competition with nitrocefin during a very short incubation (5 s).

  • d Standard deviation of 0.006 μM.

  • e Standard deviation of 0.2 μM.