Screening of Compounds for Anti-tuberculosis Activity, and in vitro and in vivo Evaluation of Potential Candidates

Wei Zhou; Bing Yang; Yanyan Zou; Khaista Rahman; Xiaojian Cao; Yingying Lei; Ren Lai; Zhen F Fu; Xi Chen; Gang Cao

doi:10.3389/fmicb.2021.658637

Screening of Compounds for Anti-tuberculosis Activity, and in vitro and in vivo Evaluation of Potential Candidates

Front Microbiol. 2021 Jun 30:12:658637. doi: 10.3389/fmicb.2021.658637. eCollection 2021.

Authors

Wei Zhou^{1

2}, Bing Yang^{1

2}, Yanyan Zou^{1

2}, Khaista Rahman^{1

2}, Xiaojian Cao^{1

2}, Yingying Lei^{1

2}, Ren Lai³, Zhen F Fu^{1

2}, Xi Chen^{1

2}, Gang Cao^{1

2

4

5}

Affiliations

¹ State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan, China.
² College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China.
³ Key Laboratory of Animal Models and Human Disease Mechanisms, Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Kunming, China.
⁴ Bio-Medical Center, Huazhong Agricultural University, Wuhan, China.
⁵ Cooperative Innovation Center for Sustainable Pig Production (CICSPPS), Huazhong Agricultural University, Wuhan, China.

Abstract

Tuberculosis (TB) is a debilitating infectious disease responsible for more than one million deaths per year. The emergence of drug-resistant TB poses an urgent need for the development of new anti-TB drugs. In this study, we screened a library of over 4,000 small molecules and found that orbifloxacin and the peptide AK15 possess significant bactericidal activity against Mycobacterium tuberculosis (Mtb) in vitro. Orbifloxacin also showed an effective ability on the clearance of intracellular Mtb and protect mice from a strong inflammatory response but not AK15. Moreover, we identified 17 nucleotide mutations responsible for orbifloxacin resistance by whole-genome sequencing. A critical point mutation (D94G) of the DNA gyrase (gyrA) gene was found to be the key role of resistance to orbifloxacin. The computational docking revealed that GyrA D94G point mutation can disrupt the orbifloxacin-protein gyrase interactions mediated by magnesium ion bridge. Overall, this study indicated the potential ability of orbifloxacin as an anti-tuberculosis drug, which can be used either alone or in combination with first-line antibiotics to achieve more effective therapy on TB.

Keywords: DNA gyrase; Mycobacterium tuberculosis; combination therapy; drug resistance; molecular docking; orbifloxacin; tuberculosis.