Discovery and preclinical profile of sudapyridine (WX-081), a novel anti-tuberculosis agent.

Multidrug resistant tuberculosis (MDR-TB) remains a major human health challenge. Bedaquiline was approved in 2012 by the US FDA, and listed by WHO as a treatment for multidrug-resistant tuberculosis (MDR-TB) in 2018. However, the side effects of bedaquiline including the risk of unexplained mortality, QTc prolongation and hepatotoxicity limit its wide clinical use. Based on bedaquiline, we describe herein discovery and development of a novel diarylpyridine series, which led to identification of WX-081 (sudapyridine, 21l). It displayed excellent anti-mycobacterial activity against M. tuberculosis H37Rv in vitro and in vivo and low cytotoxicity; additionally WX-081 had excellent pharmacokinetic parameters in animals, better lung exposure and lower QTc prolongation potential compared to bedaquiline. WX-081 is currently under clinical phase II development (NCT04608955).

Sudapyridine (WX-081) antibacterial activity against Mycobacterium avium, Mycobacterium abscessus, and Mycobacterium chelonae in vitro and in vivo.

Sudapyridine (WX-081) is a structural analog of bedaquiline (BDQ), which shows anti-tuberculosis and non-tuberculous mycobacteria (NTM) activities but, unlike BDQ, did not prolong QT interval in animal model studies. This study evaluated the antibacterial activity of this novel compound against Mycobacterium avium, Mycobacterium abscessus, and Mycobacterium chelonae in vitro and in vivo. The minimum inhibitory concentration (MIC) of WX-081 against three kinds of non-tuberculous mycobacteria (NTM) clinical strains was determined using microplate-based alamarBlue assay (MABA), and the antibacterial activity of WX-081 against NTM in J774A.1 cells and mice was evaluated. MIC ranges of WX-081 against clinical strains of M. avium and M. abscessus were 0.05-0.94 µg/mL, 0.88-7.22 µg/mL (M. abscessus subsp. abscessus), and 0.22-8.67 µg/mL (M. abscessus subsp. massiliense), respectively, which were slightly higher than those of BDQ. For M. avium, M. abscessus, and M. chelonae, WX-081 can reduce the intracellular bacterial load by 0.13-1.18, 0.18-1.50, and 0.17-1.03 log10 colony forming units (CFU)/mL, respectively, in a concentration-dependent manner. WX-081 has bactericidal activity against three NTM species in mice. WX-081 exhibited anti-NTM activity to the same extent as BDQ both in vivo and in vitro. WX-081 is a promising clinical candidate and should be studied further in clinical trials. IMPORTANCE: Due to the rapidly increased cases globally, non-tuberculous mycobacteria (NTM) disease has become a significant public health problem. NTM accounted for 11.57% of all mycobacterial isolates in China, with a high detection rate of Mycobacterium abscessus, Mycobacterium avium, and Mycobacterium chelonae during 2000-2019. Treatment of NTM infection is often challenging, as natural resistance to most antibiotics is quite common among different NTM species. Hence, identifying highly active anti-NTM agents is a priority for potent regimen establishment. The pursuit of new drugs to treat multidrug-resistant tuberculosis may also identify some agents with strong activity against NTM. Sudapyridine (WX-081) is a structural analog of bedaquiline (BDQ), which was developed to retain the anti-tuberculosis efficacy but eliminates the severe side effects of BDQ. This study initially evaluated the antimicrobial activity of this novel compound against M. avium, M. abscessus, and M. chelonae in vitro, in macrophages and mice, respectively.

Sudapyridine (WX-081), a Novel Compound against Mycobacterium tuberculosis.

Bedaquiline (BDQ) was historically listed by the World Health Organization (WHO) in 2018 as the preferred option for rifampin-resistant tuberculosis (RR-TB) and multidrug-resistant tuberculosis (MDR-TB). However, when there is no other effective regimen, the side effects and weaknesses of BDQ limit its use of MDR-TB. There is a black box warning in the package insert of BDQ to warn patients and health care professionals that this drug may increase the risk of unexplained mortality and QT prolongation, which may lead to abnormal and potentially fatal cardiac rhythm. In addition, the phenomenon of elevated liver enzymes in clinical trials of BDQ is a potential sign of hepatotoxicity. Therefore, it is still a medical need to develop new compounds with better safety profiles, patient compliance, affordability, and the ability to retain the efficacy of BDQ. After extensive lead generation and optimization, a new analog, sudapyridine (WX-081), was selected as a potential new antituberculosis candidate to move into clinical trials. Here, we evaluated WX-081's overall preclinical profile, including efficacy, pharmacokinetics, and toxicology. The in vitro activity of WX-081 against drug-sensitive and drug-resistant tuberculosis was comparable to that of BDQ, and there was comparable efficacy between WX-081 and BDQ in both acute and chronic mouse tuberculosis models using low-dose aerosol infection. Moreover, WX-081 improved pharmacokinetic parameters and, more importantly, had no adverse effects on blood pressure, heart rate, or qualitative ECG parameters from nonclinical toxicology studies. WX-081 is under investigation in a phase 2 study in patients. IMPORTANCE This study is aimed at chemotherapy for multidrug-resistant tuberculosis (MDR-TB), mainly to develop new anti-TB drugs to kill Mycobacterium tuberculosis, a microorganism with strong drug resistance. In this study, the structure of a potent antituberculosis compound, bedaquiline (BDQ), was optimized to generate a new compound, sudapyridine (WX-081). This experiment showed that its efficacy was similar to that of BDQ, its cardiotoxicity was lower, and it had good kinetic characteristics. This compound will certainly achieve significant results in the control and treatment of tuberculosis in the future.