Zhang Ying, Shi Wanliang, Zhang Wenhong, Mitchison Denis
Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland 21205, USA ; Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China.
Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland 21205, USA.
Microbiol Spectr. 2013;2(4):1-12. doi: 10.1128/microbiolspec.MGM2-0023-2013.
PZA is a unique anti-tuberculosis drug that plays a key role in shortening the TB therapy. PZA kills non-replicating persisters that other TB drugs fail to kill, and thus making it an essential drug for inclusion in any drug combinations for treating drug susceptible and drug-resistant TB such as MDR-TB. PZA acts differently from common antibiotics by inhibiting multiple targets such as energy production, trans-translation and perhaps pantothenate /coenzyme A required for persister survival. Resistance to PZA is mostly caused by mutations in the pncA gene encoding pyrazinamidase involved in conversion of the prodrug PZA to the active form POA. Mutations in the drug target RpsA are also found in some PZA-resistant strains. The recent finding that panD mutations are found in some PZA-resistant strains without pncA or rpsA mutations may suggest a third PZA resistance gene and a potential new target of PZA. Current phenotype based PZA susceptibility testing is not reliable due to false resistance, and sequencing of the pncA gene represents a more rapid, cost-effective and more reliable molecular test for PZA susceptibility testing and should be used for guiding improved treatment of MDR/XDR-TB. Finally, the story of PZA has important implications for not only TB therapy but also chemotherapy in general. PZA serves as a model prototype persister drug and hopefully a 'tipping point' that inspires new efforts at developing a new type of antibiotics or drugs that target non-replicating persisters for improved treatment of not only TB but also other persistent bacterial infections.
吡嗪酰胺是一种独特的抗结核药物，在缩短结核病治疗疗程中发挥关键作用。吡嗪酰胺能杀死其他抗结核药物无法杀灭的非复制性持留菌，因此是治疗药物敏感型和耐药型结核病（如耐多药结核病）的任何药物组合中必不可少的药物。吡嗪酰胺的作用机制与普通抗生素不同，它通过抑制多个靶点发挥作用，如能量产生、翻译后转运，或许还包括持留菌存活所需的泛酸盐/辅酶A。对吡嗪酰胺的耐药性主要由编码吡嗪酰胺酶的pncA基因突变引起，该酶参与前体药物吡嗪酰胺向活性形式吡嗪酸的转化。在一些耐吡嗪酰胺菌株中还发现了药物靶点RpsA的突变。最近的研究发现，在一些没有pncA或RpsA突变的耐吡嗪酰胺菌株中存在panD突变，这可能提示存在第三个吡嗪酰胺耐药基因以及吡嗪酰胺潜在的新靶点。由于存在假耐药性，目前基于表型的吡嗪酰胺药敏试验不可靠，而pncA基因测序是一种更快速、更具成本效益且更可靠的吡嗪酰胺药敏分子检测方法，应用于指导耐多药/广泛耐药结核病的优化治疗。最后，吡嗪酰胺的故事不仅对结核病治疗，而且对一般化疗都具有重要意义。吡嗪酰胺是一种典型的持留菌药物，有望成为一个“转折点”，激发人们努力开发新型抗生素或靶向非复制性持留菌的药物，以改善结核病及其他持续性细菌感染的治疗。
