Metabolic Profiles of Clinical Isolates of Drug-Susceptible and Multidrug-Resistant Mycobacterium tuberculosis: A Metabolomics-Based Study

Li Wang; Ruoyan Ying; Yidian Liu; Qin Sun; Wei Sha

doi:10.2147/IDR.S405987

Metabolic Profiles of Clinical Isolates of Drug-Susceptible and Multidrug-Resistant Mycobacterium tuberculosis: A Metabolomics-Based Study

Infect Drug Resist. 2023 May 3:16:2667-2680. doi: 10.2147/IDR.S405987. eCollection 2023.

Authors

Li Wang^{1

2}, Ruoyan Ying³, Yidian Liu^{1

2}, Qin Sun^{1

2

3}, Wei Sha^{1

2

3}

Affiliations

¹ Clinic and Research Center of Tuberculosis, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, People's Republic of China.
² Department of Tuberculosis, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, People's Republic of China.
³ Shanghai Key Laboratory of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, People's Republic of China.

Abstract

Background: Mycobacterium tuberculosis (MTB) is a global and highly deleterious pathogen that creates an enormous pressure on global public health. Although several effective drugs have been used to treat tuberculosis, the emergence of multidrug-resistant Mycobacterium tuberculosis (MDR-MTB) has further increased the public health burden. The aim of this study was to describe in depth the metabolic changes in clinical isolates of drug-susceptible Mycobacterium tuberculosis (DS-MTB) and MDR-MTB and to provide clues to the mechanisms of drug resistance based on metabolic pathways.

Methods: Based on the minimum inhibition concentration (MIC) of multiple anti-tuberculosis drugs, two clinical isolates were selected, one DS-MTB isolate (isoniazid MIC=0.06 mg/L, rifampin MIC=0.25 mg/L) and one MDR-MTB isolate (isoniazid MIC=4 mg/L, rifampin MIC=8 mg/L). Through high-throughput metabolomics, the metabolic profiles of the DS-MTB isolate and the MDR-MTB isolate and their cultured supernatants were revealed.

Results: Compared with the DS-MTB isolate, 128 metabolites were significantly altered in the MDR-MTB isolate and 66 metabolites were significantly altered in the cultured supernatant. The differential metabolites were significantly enriched in pyrimidine metabolism, purine metabolism, nicotinate and nicotinamide metabolism, arginine acid metabolism, and phenylalanine metabolism. Furthermore, metabolomics analysis of the bacterial cultured supernatants showed a significant increase in 10 amino acids (L-citrulline, L-glutamic acid, L-aspartic acid, L-norleucine, L-phenylalanine, L-methionine, L-tyrosine, D-tryptophan, valylproline, and D-methionine) and a significant decrease in 2 amino acids (L-lysine and L-arginine) in MDR-MTB isolate.

Conclusion: The present study provided a metabolite alteration profile as well as a cultured supernatant metabolite alteration profile of MDR-MTB clinical isolate, providing clues to the potential metabolic pathways and mechanisms of multidrug resistance.

Keywords: Mycobacterium tuberculosis; drug-susceptibleMycobacterium tuberculosis; metabolic pathway; metabolomics; multidrug-resistantMycobacterium tuberculosis.

Grants and funding

This study was funded by: Shanghai 2020 “Science and technology innovation action plan” technological innovation fund:Clinical Study on New Short-Course treatment regimens and Host-Directed Therapy for MDR-TB (20Z11900500). Shanghai Clinical Research Center for infectious disease (tuberculosis) (Grant ID:19MC1910800). The three-year action plan for promoting clinical skills and clinical innovation in municipal hospitals of Shanghai Shenkang 2020–2022 (Grant ID: SHDC2020CR6024). National Natural Science Foundation of China (Nos.82102251). Shanghai key clinical specialty construction project - Tuberculosis department (Shslczdzc03001).