Screening Repurposed Antiviral Small Molecules as Antimycobacterial Compounds by a Lux-Based phoP Promoter-Reporter Platform

• Main Authors: Li Zhu (Author), Annie Wing-Tung Lee (Author), Kelvin Ka-Lok Wu (Author), Peng Gao (Author), Kingsley King-Gee Tam (Author), Rahim Rajwani (Author), Galata Chala Chaburte (Author), Timothy Ting-Leung Ng (Author), Chloe Toi-Mei Chan (Author), Hiu Yin Lao (Author), Wing Cheong Yam (Author), Richard Yi-Tsun Kao (Author), Gilman Kit Hang Siu (Author)
• Format: Book
• Published: MDPI AG, 2022-03-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.
• Notes: 10.3390/antibiotics11030369; 2079-6382
• Keywords: <i>lux</i>-based promoter-reporter platforms; small-molecule compounds; <i>Mycobacterium tuberculosis</i> complex; anti-virulence agents; antibiotics; Therapeutics. Pharmacology; RM1-950
• Source: Antibiotics, Vol 11, Iss 3, p 369 (2022)

The emergence of multidrug-resistant strains and hyper-virulent strains of <i>Mycobacterium tuberculosis</i> are big therapeutic challenges for tuberculosis (TB) control. Repurposing bioactive small-molecule compounds has recently become a new therapeutic approach against TB. This study aimed to identify novel anti-TB agents from a library of small-molecule compounds via a rapid screening system. A total of 320 small-molecule compounds were used to screen for their ability to suppress the expression of a key virulence gene, <i>phop</i>, of the <i>M. tuberculosis</i> complex using luminescence (<i>lux</i>)-based promoter-reporter platforms. The minimum inhibitory and bactericidal concentrations on drug-resistant <i>M. tuberculosis</i> and cytotoxicity to human macrophages were determined. RNA sequencing (RNA-seq) was conducted to determine the drug mechanisms of the selected compounds as novel antibiotics or anti-virulent agents against the <i>M. tuberculosis</i> complex. The results showed that six compounds displayed bactericidal activity against <i>M. bovis</i> BCG, of which Ebselen demonstrated the lowest cytotoxicity to macrophages and was considered as a potential antibiotic for TB. Another ten compounds did not inhibit the in vitro growth of the <i>M. tuberculosis</i> complex and six of them downregulated the expression of phoP/R significantly. Of these, ST-193 and ST-193 (hydrochloride) showed low cytotoxicity and were suggested to be potential anti-virulence agents for <i>M. tuberculosis</i>.