Multi-omics comparisons of p-aminosalicylic acid (PAS) resistance in folC mutated and un-mutated Mycobacterium tuberculosis strains

ABSTRACTp-Aminosalicylic acid (PAS) is an important second-line antibiotic for treating multidrug-resistant tuberculosis (MDR-TB). Due to gastrointestinal disturbance and intolerance, its potent and efficacy in the treatment of extensively drug-resistant (XDR)-TB commonly are poor. Thus, it is important to reveal the mechanism of susceptibility and resistance of Mycobacterium tuberculosis (Mtb) to this drug. Herein, we screened and established PAS-resistant (PASr) folC mutated and un-mutated Mtb strains, then utilized a multi-omics (genome, proteome, and metabolome) analysis to better characterize the mechanisms of PAS resistance in Mtb. Interestingly, we found that promotion of SAM-dependent methyltransferases and suppression of PAS uptake via inhibiting some drug transport associated membrane proteins were two key pathways for the folC mutated strain evolving into the PASr Mtb strain. However, the folC un-mutated strain was resistant to PAS via uptake of exogenous methionine, mitigating the role of inhi...