Nosiheptide Harbors Potent In Vitro and Intracellular Inhbitory Activities against Mycobacterium tuberculosis.

Abstract

Multidrug-resistant tuberculosis (MDR-TB) is often associated with poor clinical outcomes. In this study, we evaluated the potential of nosiheptide (NOS) as a new drug candidate for treating Mycobacterium tuberculosis infections, including MDR-TB. The antimicrobial susceptibility testing was performed to determine the MICs of NOS against 18 reference strains of slowly growing mycobacteria (SGM) and 128 clinical isolates of M. tuberculosis. The postantibiotic effects (PAE) and interaction with other antituberculosis drugs of NOS were also evaluated using M. tuberculosis H37Rv. Fifteen out of the 18 tested reference strains of SGM had MICs far below 1 μg/mL. From the 128 M. tuberculosis clinical isolates, the MIC50 and MIC90 were 0.25 μg/mL and 1 μg/mL, respectively; the tentative epidemiological cutoff (ECOFF) was defined at 1 μg/mL. Furthermore, a Lys89Thr mutation was found in one M. tuberculosis isolate with a MIC of NOS >8 μg/mL. After 24 h of incubation, NOS at 1 μg/mL inhibited 25.79 ± 1.22% of intracellular bacterial growth, which was comparable with the inhibitory rate of 25.71 ± 3.67% achieved by rifampin at 2 μg/mL. Compared to rifampicin and isoniazid (INH), NOS had a much longer PAE, i.e., a value of about 16 days. In addition, a partial synergy between NOS and INH was observed. NOS has potent inhibitory activities against M. tuberculosis in vitro as well as in macrophages. Furthermore, the long PAE and partial synergistic effect with INH, in addition to the added safety of long-term use as a feed additive in husbandry, provide support for NOS being a promising drug candidate for tuberculosis treatment. IMPORTANCE This study is aimed at chemotherapy for MDR-TB, mainly to explore the anti-TB activity of the existing chemotherapeutic reagent. We found that NOS has potent inhibitory activities against M. tuberculosis in vitro regardless of the drug-resistant profile. Furthermore, NOS also showed the long PAE and partial synergistic effect with INH and is nontoxic, providing support for its promise as a drug candidate for drug-resistant tuberculosis treatment.

• Authors: Xia Yu, Rui Zhu, Zhi Geng, Yaoyao Kong, Fen Wang, Lingling Dong, Liping Zhao, Yi Xue, Xiaochi Ma, Hairong Huang
• Journal: Microbiology spectrum (Microbiol Spectr) Vol. 10 Issue 6 Pg. e0144422 (12 21 2022) ISSN: 2165-0497 [Electronic] United States
• PMID: 36222690 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• nosiheptide
• Antitubercular Agents
• Isoniazid
• Rifampin
• Mitomycin

Topics

• Humans
• Mycobacterium tuberculosis (genetics)
• Antitubercular Agents (pharmacology, therapeutic use)
• Isoniazid (pharmacology)
• Tuberculosis, Multidrug-Resistant (drug therapy, microbiology)
• Rifampin (pharmacology, therapeutic use)
• Microbial Sensitivity Tests
• Mitomycin (pharmacology, therapeutic use)