Identification of Mutations Conferring Tryptanthrin Resistance to <i>Mycobacterium smegmatis</i>

• Main Authors: Svetlana G. Frolova (Author), Ksenia M. Klimina (Author), Ravinder Kumar (Author), Aleksey A. Vatlin (Author), Deepak B. Salunke (Author), Pravin Kendrekar (Author), Valery N. Danilenko (Author), Dmitry A. Maslov (Author)
• Format: Book
• Published: MDPI AG, 2020-12-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.
• Notes: 10.3390/antibiotics10010006; 2079-6382
• Keywords: tuberculosis; mycobacterium smegmatis; tryptanthrin; drug resistance; efflux; Therapeutics. Pharmacology; RM1-950
• Source: Antibiotics, Vol 10, Iss 1, p 6 (2020)

Tuberculosis (TB), caused by <i>Mycobacterium tuberculosis</i>, is a global burden, responsible for over 1 million deaths annually. The emergence and spread of drug-resistant <i>M. tuberculosis</i> strains (MDR-, XDR- and TDR-TB) is the main challenge in global TB-control, requiring the development of novel drugs acting on new biotargets, thus able to overcome the drug-resistance. Tryptanthrin is a natural alkaloid, with great therapeutic potential due to its simple way of synthesis and wide spectrum of biological activities including high bactericidal activity on both drug-susceptible and MDR <i>M. tuberculosis</i> strains. InhA was suggested as the target of tryptanthrins by in silico modeling, making it a promising alternative to isoniazid, able to overcome drug resistance provided by <i>katG</i> mutations. However, neither the mechanism of action of tryptanthrin nor the mechanism of resistance to tryptanthrins was ever confirmed in vitro. We show that the MmpS5-MmpL5 efflux system is able to provide resistance to tryptanthrins using an in-house test-system. Comparative genomic analysis of spontaneous tryptanthrin-resistant <i>M. smegmatis</i> mutants showed that mutations in <i>MSMEG_1963</i> (EmbR transcriptional regulator) lead to a high-level resistance, while those in <i>MSMEG_5597</i> (TetR transcriptional regulator) to a low-level one. Mutations in an MFS transporter gene (<i>MSMEG_4427</i>) were also observed, which might be involved in providing a basal level of tryptanthrins-resistance.