Shuai Guo, Changwei Kou, Shiguang Pan, Yan Lv, Eied Saber Alamain Ali, Fatemeh Dehghan, Mahlagha Dehghan
In the recent decades, Non-tuberculous mycobacteria (NTM) have posed an emerging clinical threat. The treatment of NTM infection poses therapeutic challenges owing to factors like drug-resistance of pathogens, presence of biofilms, and the time-consuming treatment regimens. Given high toxicity and limited efficacy of numerous established therapeutic agents, natural products have been explored extensively as alternative or adjuvant therapy for NTM. This systematic review focused on therapeutic benefits of natural products in NTM infection. Major biomedical literature databases (PubMed, Scopus, Web of Science, Embase, Cochrane Library, Google Scholar) were searched for publications till December 2025 to collect relevant articles detailing the impact of natural products on NTM organisms. We included in vitro studies, in vivo studies (animal models) and clinical trials that assessed the antimycobacterial actions of diverse natural product types. The quality and risk of bias have been appraised utilizing standard tools like ToxRTool and SYRCLE to evaluate the methodological rigor of the selected articles. Total of 19 studies were selected, the majority of which (n = 15) were laboratory-based. A variety of agents such as essential oils, isolated phytochemicals, and probiotics showed antimycobacterial activities targeting different NTM species such as M. avium and M. abscessus complexes. Several compounds such as Juniperus communis essential oil, Helichrysum italicum essential oil, berberine combinations, and citrus oil fractions, demonstrated significant activity when combined with conventional antimycobacterial agents or through the disruption of biofilm formation. Animal and clinical studies revealed less conclusive benefits, while few showed improved immunity or stable imaging, and substantial reduction in bacterial load was rarely achieved. Overall, the quality of current research is inconsistent, and further rigorous validation is needed. Although natural products show promise as antimycobacterial agents and their adjunctive actions in vitro, their clinical success remains limited and significant improvement is expected. Future rigorously planned experimental and clinical studies will need to validate the therapeutic role of these promising products in NTM management.