关键词: 分枝杆菌,结核, 药物靶标, 耐药机制, 药物基因组学

Abstract:

Tuberculosis, as a global public health challenge, faces severe tests in treatment due to the issue of drug resistance. Current research and development of anti-tuberculosis drugs focus on key targets such as mycobacterial cell wall synthesis (e.g., the mycolic acid synthesis pathway), energy metabolism, protein synthesis and degradation, DNA replication and repair, and host immune regulation. In the field of mycolic acid synthesis, Pks13-TE inhibitors (such as compound 44, N-aryl indole derivatives), non-covalent DprE1 inhibitors, and MmpL3 transporter inhibitors (indole-2-carboxamide compounds) have demonstrated high antibacterial activity. Studies on resistance mechanisms have found that the activation of nitroimidazole drugs depends on Rv0077c metabolic regulation, and folate pathway Rv2172c mutations mediate PAS resistance through methionine accumulation. Emerging technologies like CRISPRi enhance antibiotic efficacy by inhibiting the inhA gene, and PROTAC technology reduces bacterial survival by degrading the ClpC1 protein. Pharmacogenomics has revealed that NAT2 acetylation phenotypes and ATP7B genotypes significantly affect the risk of isoniazid-induced hepatotoxicity, and HLA-DPB1 alleles are associated with drug side effects. The short-course chemotherapy regimen BpaL (bedaquiline, pretomanid, linezolid) shows significant efficacy (90% cure rate) but has severe side effects; alternative regimens BpaS (spectinamide 1599) and TBI-223 combinations exhibit better safety profiles. Future research trends emphasize multi-target combination therapy, precision intervention in resistance mechanisms, and optimization of molecular diagnostic techniques to achieve the efficiency and individualization of tuberculosis treatment.

Key words: Mycobacterium tuberculosis, Drug targets, Resistance mechanisms, Pharmacogenomics