Davis W B, Weber M M
Antimicrob Agents Chemother. 1977 Aug;12(2):213-8. doi: 10.1128/AAC.12.2.213.
The mechanism of action of isoniazid (INH) on saprophytic and atypical mycobacteria is thought to be different from that on Mycobacterium tuberculosis because higher concentrations are required to be effective in these species. In this investigation, M. phlei was inhibited by INH at a concentration of 25 mug/ml. Benzoic acid hydrazide (BZH) and nicotinic acid hydrazide (NAH) were inhibitory at levels of 300 and 500 mug/ml, respectively. Inhibition by these compounds was not inoculum dependent. An isolated M. phlei mutant resistant to 100 mug of INH per ml (Inh(r)) was inhibited by INH only at concentrations about equal to those inhibitory for BZH and NAH. When NAH and BZH were below their minimal inhibitory concentrations, INH inhibition was antagonized. Hence, there appears to be a single target site for INH in mycobacteria with different affinities for various hydrazide analogs of INH. The increased inhibitory levels required for the atypical and saprophytic species are due to a decreased affinity of the target site for INH in these species. INH also inhibited both the oxidized nicotinamide adenine dinucleotide (NAD(+)) and adenosine 5'-monophosphate stimulation of reduced NAD (NADH) oxidase activity associated with the M. phlei and M. tuberculosis H(37)R(a) electron transport particles. INH did not reverse the NAD(+) stimulation of oxidase activity in the Inh(r) strain of M. phlei. No direct inhibitory effect of INH on NADH oxidase activity was observed. Incubation of M. phlei electron transport particles at 0 degrees C with INH resulted in a dramatic loss of oxidase activity which could have been prevented if NAD(+) were present. However, INH had no effect upon the NADH oxidase when stored with electron transport particles isolated from the Inh(r) strain. Therefore, INH inhibition of regulation and/or stabilization of the electron transport pathway by NAD(+) or adenosine 5'-monophosphate may account, in part, for the lethal action of the drug on mycobacteria.
异烟肼（INH）对腐生型和非典型分枝杆菌的作用机制被认为与对结核分枝杆菌的作用机制不同，因为在这些菌属中需要更高的浓度才能产生效果。在本研究中，草分枝杆菌在25微克/毫升的INH浓度下受到抑制。苯甲酸酰肼（BZH）和烟酸酰肼（NAH）分别在300和500微克/毫升的水平具有抑制作用。这些化合物的抑制作用不依赖于接种量。一株对每毫升100微克INH耐药的草分枝杆菌突变株（Inh(r)）仅在与BZH和NAH抑制浓度大致相等的浓度下被INH抑制。当NAH和BZH低于其最小抑制浓度时，INH的抑制作用被拮抗。因此，在分枝杆菌中似乎存在一个INH的单一靶点，其对INH的各种酰肼类似物具有不同的亲和力。非典型和腐生型菌属所需的抑制水平增加是由于这些菌属中靶点对INH的亲和力降低。INH还抑制了与草分枝杆菌和结核分枝杆菌H(37)R(a)电子传递颗粒相关的还原型烟酰胺腺嘌呤二核苷酸（NADH）氧化酶活性对氧化型烟酰胺腺嘌呤二核苷酸（NAD(+)）和5'-单磷酸腺苷的刺激。INH不能逆转草分枝杆菌Inh(r)菌株中氧化酶活性对NAD(+)的刺激。未观察到INH对NADH氧化酶活性有直接抑制作用。将草分枝杆菌电子传递颗粒在0℃下与INH孵育会导致氧化酶活性急剧丧失，如果存在NAD(+)，这种情况本可避免。然而，当与从Inh(r)菌株分离的电子传递颗粒一起储存时，INH对NADH氧化酶没有影响。因此，INH通过NAD(+)或5'-单磷酸腺苷对电子传递途径的调节和/或稳定作用的抑制可能部分解释了该药物对分枝杆菌的致死作用。
