PA-824 is a nitroimidazole anti-tuberculosis drug. PA-824 kills bacteria by inhibiting Mycobacterium tuberculosis cell wall synthesis and interfering with energy metabolism[1-2]. PA-824 can be used in research related to multidrug-resistant tuberculosis and extensively drug-resistant tuberculosis[3-4].
In vitro, PA-824 (2.5-10µg/ml) was used to treat M. leprae and M. tuberculosis for 7 days. PA-824 had no effect on the viability of M. leprae, PA-824 significantly reduced the proliferation of M. tuberculosis[5]. PA-824 (0.015-16µg/ml) was used to treat M. avium, M. intracellulare, M. abscessus, and M. massiliense for 3-14 days. The inhibitory effect of PA-824 on these five mycobacterial species was generally weak, with minimum inhibitory concentration (MIC) values all greater than 16µg/ml[6].
In vivo, PA-824 (200mg/kg/day) was administered by oral gavage to BALB/c mice infected with M. avium, M. abscessus, M. chelonae, or M. fortuitum (once daily, starting 7 days after infection, for 28 days). PA-824 demonstrated strong antibacterial activity in the lungs and spleens of mice infected with M. abscessus, and weak activity in the kidneys of mice infected with M. fortuitum. PA-824 showed no significant antibacterial effect in the mouse models infected with M. avium or M. chelonae[7]. PA-824 (40-80mg/kg/day) was administered by oral gavage to Tg.rasH2 mice (once daily for 26 weeks). The mice, exposed to PA-824 at levels exceeding the clinical human exposure dose, did not exhibit drug-related early death, tumors, or non-tumorigenic microscopic pathological changes[8].
References:
[1] Keam SJ. Pretomanid: First Approval. Drugs. 2019 Nov;79(16):1797-1803. doi: 10.1007/s40265-019-01207-9.
[2] Gils T, Lynen L, de Jong BC, et al. Pretomanid for tuberculosis: a systematic review. Clin Microbiol Infect. 2022 Jan;28(1):31-42.
[3] Deb U, Biswas S. Pretomanid: The latest USFDA-approved anti-tuberculosis drug. Indian J Tuberc. 2021 Apr;68(2):287-291.
[4] Koehler N, Andres S, Merker M, et al. Pretomanid-resistant tuberculosis. J Infect. 2023 May;86(5):520-524.
[5] Manjunatha UH, Lahiri R, Randhawa B, et al. Mycobacterium leprae is naturally resistant to PA-824. Antimicrob Agents Chemother. 2006 Oct;50(10):3350-4.
[6] Zheng H, Wang Y, He W, et al. In Vitro Activity of Pretomanid against Nontuberculous Mycobacteria. Antimicrob Agents Chemother. 2022 Jan 18;66(1):e0181021.
[7] Zheng L, Qi X, Zhang W, et al. Efficacy of PBTZ169 and pretomanid against Mycobacterium avium, Mycobacterium abscessus, Mycobacterium chelonae, and Mycobacterium fortuitum in BALB/c mice models. Front Cell Infect Microbiol. 2023 Mar 22;13:1115530.
[8] Ambroso JL, Dillberger J, Bruning-Barry R, et al. Assessment of the Carcinogenic Potential of Pretomanid in Transgenic Tg.rasH2 Mice. Int J Toxicol. 2022 Sep-Oct;41(5):367-379.
PA-824是一种硝基咪唑类抗结核药物，PA-824可通过抑制结核分枝杆菌细胞壁合成和干扰能量代谢来杀灭细菌[1-2]。PA-824可用于多重耐药结核病和广泛耐药结核病的相关研究[3-4]。
在体外，PA-824（2.5-10μg/ml）在处理麻风分枝杆菌和结核分枝杆菌7天，PA-824对麻风分枝杆菌的活力没有影响，PA-824可显著降低结核分枝杆菌的增殖[5]。PA-824（0.015-16μg/ml）处理鸟分枝杆菌、胞内分枝杆菌、脓肿分枝杆菌和马赛分枝杆菌3-14天，PA-824对这五种分枝杆菌的抑制效果一般，最小抑菌浓度（MIC）都大于16μg/ml[6]。
在体内，PA-824（200mg/kg/day）灌胃处理感染鸟分枝杆菌、脓肿分枝杆菌、龟分枝杆菌或偶发分枝杆菌的BALB/c小鼠（每日一次，从感染后第7天开始，持续28天），PA-824在脓肿分枝杆菌感染小鼠的肺部和脾脏显示出较强的抗菌活性，在偶发分枝杆菌感染小鼠的肾脏显示出较弱的抗菌活性，但在鸟分枝杆菌和龟分枝杆菌感染模型中未显示出显著的抗菌效果[7]。PA-824（40-80mg/kg/day）灌胃处理Tg.rasH2小鼠（每日一次，持续26周），小鼠在高于人用临床暴露剂量的PA-824暴露水平下，未出现药物相关的早期死亡、肿瘤或非肿瘤性微观病理改变的现象[8]。