The Antitubercular Activities of Natural Products with Fused-Nitrogen-Containing Heterocycles

Abstract

Tuberculosis (TB) is notorious as the leading cause of death worldwide due to a single infectious entity and its causative agent, Mycobacterium tuberculosis (Mtb), has been able to evolve resistance to all existing drugs in the treatment arsenal complicating disease management programs. In drug discovery efforts, natural products are important starting points in generating novel scaffolds that have evolved to specifically bind to vulnerable targets not only in pathogens such as Mtb, but also in mammalian targets associated with human diseases. Structural diversity is one of the most attractive features of natural products. This review provides a summary of fused-nitrogen-containing heterocycles found in the natural products reported in the literature that are known to have antitubercular activities. The structurally targeted natural products discussed in this review could provide a revealing insight into novel chemical aspects with novel biological functions for TB drug discovery efforts.

Not only ClpC1 but also ClpX are drug targets of Ilamycins

“…Specifically, rufomycin I inhibited Mtb growth at a MIC of 60 nM by day 14 when tested with the autoluminescent Mtb strain, while ILE achieves an MIC of 48 nM (equivalent to 0.05 µg/mL) by day 15 (Figure 1A) (Shetye et al, 2021). Moreover, the MIC of ILE is significantly lower than those of cyclomarin A (100 nM), ecumicin (160 nM), and lassomycin (410 nM) reported (Gavrish et al, 2014;Boshoff et al, 2024). While these compounds exhibit activity against a range of NTM, only rufomycin I and ILE exhibit efficacy against Mab, indicating their potential as therapeutic agents for diseases caused by Mab .…”

“…Many non-ribosomal natural cyclic peptides, such as ilamycins (also known as rufomycins), cyclomarins, and ecumicins, have shown antitubercular activities by targeting the ClpC1 component of the ClpC1P1P2 proteasome (Boshoff et al, 2024). However, aside from the mutations identified in the clpC1 gene from spontaneous resistant mutants, robust genetic evidence is lacking.…”

“…We previously reported that ilamycin E (ILE) and ilamycin F (ILF), synthesized by Streptomyces atratus SCSIO ZH16 isolated from the South China Sea, exhibited activities against Mtb (Ma et al, 2017). Particularly, ILE demonstrated superior activity against Mtb compared to other ilamycin components and the aforementioned compounds (Gavrish et al, 2014;Ma et al, 2017;Boshoff et al, 2024). However, their MOAs, activities against NTM and other non-mycobacterial pathogenic bacteria, and potential drug interactions remain to be elucidated.…”