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

Abstract

p -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 (PAS r ) 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 PAS r Mtb strain. However, the folC un-mutated strain was resistant to PAS via uptake of exogenous methionine, mitigating the role of inhibitors, and promoting DfrA, ThyA and FolC expression. Beyond these findings, we also found PAS resistance in Mtb might be associated with the increasing phenylalanine metabolism pathway. Collectively, our findings uncovered the differences of resistant mechanism between folC mutated and un-mutated Mtb strains resistant to PAS using multi-omics analysis and targeting modulators to these pathways may be effective for treatment of PAS r Mtb strains.

Mutations of folC cause increased susceptibility to sulfamethoxazole in Mycobacterium tuberculosis

“…Very recently, researchers found that in PAS-resistant clinical isolates of M. tuberculosis with folC mutation, protein expression levels of folP2 were significantly lower than in strains with no folC mutation 28 . Though FolP2 of M. tuberculosis has been predicted to be defective in dihydropteroate synthesis activity 27 , deletion of the folP2 gene in M. smegmatis resulted in increased susceptibility to SMX 26 .…”

Omics Biomarkers for Monitoring Tuberculosis Treatment: A Mini-Review of Recent Insights and Future Approaches

“… 35 The integromics data analysis is also performed to reveal the MTB resistance mechanism due to p-aminosalicylic acid for MDR-TB and XDR-TB treatment. 36 …”

Drug-Resistant Tuberculosis 2020: Where We Stand

“…Many excellent reviews report the genetic mechanisms involved in this resistance to RIF, INH, KM, CP and other drugs [18,23,24,98,118,126]. [106,107] ubiA Phosphoribosyltransferase (cell wall synthesis) [108,109] DLM ddn Deazaflavin (F 420 )-dependent nitroreductase (mycolic acid synthesis) [110] fgd-1 Glucose-6-phosphate dehydrogenase (F 420 synthesis) [110] fbiA Protein FbiA (F 420 synthesis) [110] fbiB Protein FbiB (F 420 synthesis) [110] fbiC Protein FbiC (F 420 synthesis) [110] PZA pncA Pyrazinamidase (conversion of PZA into pyrazinoic acid, resulting in dysfunctions of membrane potential) [98,111] ethA Monooxygenase (activation of ETO and PTO) [19,122] mymA Monooxygenase (activation of ETO and PTO) [121,123] katG Catalase-peroxidase (activation of ETO, PTO, INH) [122] inhA Enoyl-ACP reductase (mycolic acid synthesis) [98,122] PAS thyA Thymidylate synthase [23,124] folC Dihydropholate synthase [23,125] dfrA Dihydropholate reductase [23,125] Phenotypic testing is still considered a gold standard for Mtb DST, which is accurate, but takes at least two weeks for results [98]. However, a pivotal role has been recently played by the more and more rapid molecular methods to diagnose drug-resistant TB by the identification of chromosomal mutations, including line probe assays, the Xpert MTB/RIF system (Cepheid, Sunnyvale, CA, USA), target gene sequencing, whole genome sequencing (WGS), point-of-care nucleic acid amplification devices [9,127,128].…”