Assessing capreomycin resistance on tlyA deficient and point mutation (G695A) Mycobacterium tuberculosis strains using multi-omics analysis

Capreomycin (CAP), a cyclic peptide antibiotic, is considered to be an ideal second-line drug for tuberculosis (TB). However, in the past few years, the emergence of more CAP-resistant (CAPr) TB patients has limited its use. Although it has been reported that CAP resistance to Mycobacterium tuberculosis (Mtb) is associated with rrs or tlyA mutation, the exact mechanism of CAPr Mtb strains, especially the mechanism associated with tlyA deficient or mutation, is not fully understood. Herein, we utilized a multi-omics (genome, proteome, and metabolome) approach to assess CAP resistance on tlyA deficient CAPr Mtb strains (CAPr1) and tlyA point mutation CAPr Mtb strains (CAPr2) that we established for the first time in vitro to investigate the CAP-resistant mechanism. Our results showed that the CAPr1 strains (> 40 μg/ml) was more resistant to CAP than the CAPr2 strains (G695A, 10 μg/ml). Furthermore, multi-omics analysis indicated that the CAPr1 strains exhibited greater drug tolerance than the CAPr2 strains may be associated with the weakening of S-adenosyl-L-methionine-dependent methyltransferase (AdoMet-MT) activity and abnormal membrane lipid metabolism such as suppression of fatty acid metabolism, promotion of glycolipid phospholipid and glycerolipid metabolism. As a result, these studies reveal a new mechanism for CAP resistance to tlyA deficient or mutation Mtb strains, and may be helpful in developing new therapeutic approaches to prevent Mtb resistance to CAP.