Table 2.

Rate Constants for ftuFabI Inhibition as well as In Vitro and In Vivo Antibacterial Activity of Selected Diphenyl Ethers.

Inhibitor	k2 (min−1)	k−2 (min−1)	Residence time (min)a	K1app (nM)	K1 (nM)b	MIC90 (μg/ml)	Cytotoxicity LC50 (μg/ml)c	Median Survivald	%Survivale
Triclosan (1)	0.56 ± 0.04	0.025 ± 0.003	40 ± 3	407 ± 48	0.051 ± 0.003	0.000015 ± 0	14 ± 1	7.8	22
4	0.11 ± 0.01	0.033 ± 0.002	30 ± 2	665 ± 70	1.9 ± 0.1	0.001 ± 0.001	60 ± 14	6.8	11
8	0.13 ± 0.01	0.048 ± 0.001	21 ± 1	1080 ± 110	2.1 ± 0.1	0.03 ± 0.001	65 ± 2	6.1	0
9	1.66 ± 0.01	0.017 ± 0.002	59 ± 2	375 ± 6	0.44 ± 0.02	0.00018 ± 0.00014	62 ± 3	7.8	39
11	0.90 ± 0.01	0.007 ± 0.002	143 ± 14	117 ± 2	2.7 ± 0.1	0.16 ± 0.06	101 ± 2	Undefinedf	100
control	nag	na	na	na	na	na		5.2	0

^aResidence time = 1/k_off where k_off = k₋₁k₋₂/(k₋₁+k₂+k₋₂). In the two step slow onset inhibition mechanism, k₋₁≫ k₂ and k_−2, hence k_off ≈ k₋₂ (19).

^bK₁ is the thermodynamic dissociation constant taken from Table 1.

^cCytoxicity was determined using Vero cells. Note that the maximum tolerated dose was >300 mg/kg for each compound evaluated in the animal model of infection.

^dAll drugs were delivered at 200 mg/kg i.p. once a day for 5 days starting from the day of infection and observed for an additional 5 days. Animals were sacrificed at day 10. Each study was conducted with 9 animals, and data are means for one (4 and 8), two (1 and 9) or three (11) studies. For one of the studies with 9, drug was administered i.p. at 100 mg/kg.

^e%survival is percent of animals that survived to day 10.

^fMedian survival is undefined for 11 since no animals died during the study.

^gna, not applicable.