Microbial Immunity and Pathogenesis Group, Department of Infectious Diseases and Immunology (S.E., L.L., J.A.T.), and Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute (D.S.K., M.L.H.H., D.R.R.), University of Sydney, Sydney, New South Wales, Australia; and Centre for Infectious Diseases and Microbiology, Institute of Clinical Pathology and Medical Research-Pathology West, Westmead Hospital, Sydney, New South Wales, Australia (P.J., V.S.).
Mol Pharmacol. 2014 Feb;85(2):269-78. doi: 10.1124/mol.113.090357. Epub 2013 Nov 15.
The rise in drug-resistant strains of Mycobacterium tuberculosis is a major threat to human health and highlights the need for new therapeutic strategies. In this study, we have assessed whether high-affinity iron chelators of the pyridoxal isonicotinoyl hydrazone (PIH) class can restrict the growth of clinically significant mycobacteria. Screening a library of PIH derivatives revealed that one compound, namely, 2-pyridylcarboxaldehyde isonicotinoyl hydrazone (PCIH), exhibited nanomolar in vitro activity against Mycobacterium bovis bacille Calmette-Guérin and virulent M. tuberculosis. Interestingly, PCIH is derived from the condensation of 2-pyridylcarboxaldehyde with the first-line antituberculosis drug isoniazid [i.e., isonicotinic acid hydrazide (INH)]. PCIH displayed minimal host cell toxicity and was effective at inhibiting growth of M. tuberculosis within cultured macrophages and also in vivo in mice. Further, PCIH restricted mycobacterial growth at high bacterial loads in culture, a property not observed with INH, which shares the isonicotinoyl hydrazide moiety with PCIH. When tested against Mycobacterium avium, PCIH was more effective than INH at inhibiting bacterial growth in broth culture and in macrophages, and also reduced bacterial loads in vivo. Complexation of PCIH with iron decreased its effectiveness, suggesting that iron chelation may play some role in its antimycobacterial efficacy. However, this could not totally account for its potent efficacy, and structure-activity relationship studies suggest that PCIH acts as a lipophilic vehicle for the transport of its intact INH moiety into the mammalian cell and the mycobacterium. These results demonstrate that iron-chelating agents such as PCIH may be of benefit in the treatment and control of mycobacterial infection.
结核分枝杆菌耐药株的增加对人类健康构成了重大威胁，凸显了开发新治疗策略的必要性。在这项研究中，我们评估了吡啶醛异烟酰腙（PIH）类高亲和力铁螯合剂是否可以限制临床相关分枝杆菌的生长。筛选 PIH 衍生物文库表明，一种化合物，即 2-吡啶甲醛异烟酰腙（PCIH），对牛分枝杆菌卡介苗和毒力结核分枝杆菌具有纳摩尔级别的体外活性。有趣的是，PCIH 是由 2-吡啶甲醛与一线抗结核药物异烟肼（即异烟肼酰肼（INH））缩合而成。PCIH 对宿主细胞的毒性极小，可有效抑制培养的巨噬细胞中结核分枝杆菌的生长，也可在体内抑制小鼠的生长。此外，PCIH 在培养物中高细菌负荷时限制分枝杆菌的生长，而 INH 则没有这种特性，INH 与 PCIH 共享异烟酰肼部分。在测试对鸟分枝杆菌时，PCIH 在肉汤培养和巨噬细胞中抑制细菌生长的效果比 INH 更有效，并且在体内也降低了细菌负荷。PCIH 与铁的络合降低了其有效性，表明铁螯合可能在其抗分枝杆菌疗效中起一定作用。然而，这并不能完全解释其强大的疗效，并且结构-活性关系研究表明，PCIH 作为亲脂性载体，将其完整的 INH 部分转运到哺乳动物细胞和分枝杆菌中。这些结果表明，铁螯合剂如 PCIH 可能有益于治疗和控制分枝杆菌感染。
