In Mycobacterium abscessus , the stringent factor Rel regulates metabolism, but is not the only (p)ppGpp synthase.

Abstract

The stringent response is a broadly conserved stress response system that exhibits functional variability across bacterial clades. Here, we characterize the role of the stringent factor Rel in the non-tuberculous mycobacterial pathogen, Mycobacterium abscessus ( Mab ). We found that deletion of rel does not ablate (p)ppGpp synthesis, and that rel does not provide a survival advantage in several stress conditions, or in antibiotic treatment. Transcriptional data show that Rel Mab is involved in regulating expression of anabolism and growth genes in stationary phase. However, it does not activate transcription of stress response or antibiotic resistance genes, and actually represses transcription of many antibiotic resistance genes. This work shows that there is an unannotated (p)ppGpp synthetase in Mab . Importance In this study, we examined the functional roles of the stringent factor Rel in Mycobacterium abscessus (Mab) . In most species, stringent factors synthesize the alarmone (p)ppGpp, which globally alters transcription to promote growth arrest and survival under stress and in antibiotic treatment. Our work shows that in Mab, an emerging pathogen which is resistant to many antibiotics, the stringent factor Rel is not solely responsible for synthesizing (p)ppGpp. We find that Rel Mab downregulates many metabolic genes under stress, but does not upregulate stress response genes and does not promote antibiotic tolerance. This study implies that there is another critical but unannotated (p)ppGpp synthetase in Mab, and suggests that Rel Mab inhibitors are unlikely to sensitize Mab infections to antibiotic treatment.