A Lysine Acetyltransferase Contributes to the Metabolic Adaptation to Hypoxia in Mycobacterium tuberculosis

Rittershaus, Emily S. C.; Baek, Seung‐Hun; Krieger, I.V.; Nelson, Shakira M.; Cheng, Yu‐Shan; Nambi, Subhalaxmi; Baker, Richard E.; Leszyk, John D.; Shaffer, Scott A.; Sacchettini, James C.; Sassetti, Christopher M.

doi:10.1016/j.chembiol.2018.09.009

Cited by 40 publications

(40 citation statements)

References 54 publications

(85 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Many studies investigating antibiotic efficacy and new drug target discovery are performed in vitro . While it is possible to change discrete aspects of the culture conditions to mimic individual stresses ( 25 , 45 – 48 ), these models do not fully recapitulate the complex environment encountered by the bacterial population during infection. In this study, we identified genes important for bacterial survival under antibiotic pressure in the mouse model of TB, where the bacteria grow intracellularly ( 49 ) in the presence of a fully functional adaptive immune response.…”

Section: Discussionmentioning

confidence: 99%

Distinct Bacterial Pathways Influence the Efficacy of Antibiotics against Mycobacterium tuberculosis

et al. 2020

Self Cite

View full text Add to dashboard Cite

Effective tuberculosis treatment requires at least 6 months of combination therapy. Alterations in the physiological state of the bacterium during infection are thought to reduce drug efficacy and prolong the necessary treatment period, but the nature of these adaptations remain incompletely defined. To identify specific bacterial functions that limit drug effects during infection, we employed a comprehensive genetic screening approach to identify mutants with altered susceptibility to the first-line antibiotics in the mouse model. We identified many mutations that increase the rate of bacterial clearance, suggesting new strategies for accelerating therapy. In addition, the drug-specific effects of these mutations suggested that different antibiotics are limited by distinct factors. Rifampin efficacy is inferred to be limited by cellular permeability, whereas isoniazid is preferentially affected by replication rate. Many mutations that altered bacterial clearance in the mouse model did not have an obvious effect on drug susceptibility using in vitro assays, indicating that these chemical-genetic interactions tend to be specific to the in vivo environment. This observation suggested that a wide variety of natural genetic variants could influence drug efficacy in vivo without altering behavior in standard drug-susceptibility tests. Indeed, mutations in a number of the genes identified in our study are enriched in drug-resistant clinical isolates, identifying genetic variants that may influence treatment outcome. Together, these observations suggest new avenues for improving therapy, as well as the mechanisms of genetic adaptations that limit it. IMPORTANCE Understanding how Mycobacterium tuberculosis survives during antibiotic treatment is necessary to rationally devise more effective tuberculosis (TB) chemotherapy regimens. Using genome-wide mutant fitness profiling and the mouse model of TB, we identified genes that alter antibiotic efficacy specifically in the infection environment and associated several of these genes with natural genetic variants found in drug-resistant clinical isolates. These data suggest strategies for synergistic therapies that accelerate bacterial clearance, and they identify mechanisms of adaptation to drug exposure that could influence treatment outcome.

show abstract

Section: Discussionmentioning

confidence: 99%

Distinct Bacterial Pathways Influence the Efficacy of Antibiotics against Mycobacterium tuberculosis

et al. 2020

Self Cite

View full text Add to dashboard Cite

show abstract

“…Several reports showed pellicle or pellicle-like biofilm formation in M. tuberculosis and M. smegmatis [59][60][61][62] . However, they identified groEL1, mutT3 (neighboring pknG), and malate dehydrogenase as genes that confer biofilm formation, which is contrary to our study results that identified them as non-essential with no significant fitness change under hypoxia.…”

Section: Discussionmentioning

confidence: 99%

Genome-wide identification of essential genes in Mycobacterium intracellulare by transposon sequencing — Implication for metabolic remodeling

Tateishi

Minato

Baughn

et al. 2020

Sci Rep

View full text Add to dashboard Cite

The global incidence of the human nontuberculous mycobacteria (NTM) disease is rapidly increasing. However, knowledge of gene essentiality under optimal growth conditions and conditions relevant to the natural ecology of NTM, such as hypoxia, is lacking. In this study, we utilized transposon sequencing to comprehensively identify genes essential for growth in Mycobacterium intracellulare. Of 5126 genes of M. intracellulare ATCC13950, 506 genes were identified as essential genes, of which 280 and 158 genes were shared with essential genes of M. tuberculosis and M. marinum, respectively. The shared genes included target genes of existing antituberculous drugs including SQ109, which targets the trehalose monomycolate transporter MmpL3. From 175 genes showing decreased fitness as conditionally essential under hypoxia, preferential carbohydrate metabolism including gluconeogenesis, glyoxylate cycle and succinate production was suggested under hypoxia. Virulenceassociated genes including proteasome system and mycothiol redox system were also identified as conditionally essential under hypoxia, which was further supported by the higher effective suppression of bacterial growth under hypoxia compared to aerobic conditions in the presence of these inhibitors. This study has comprehensively identified functions essential for growth of M. intracellulare under conditions relevant to the host environment. These findings provide critical functional genomic information for drug discovery.

show abstract

“…Reverse lysine acetylation and Ser/Thr/Tyr phosphorylation have broad regulatory functions, and lysine acetyltransferases and protein kinases were previously reported to play pivotal roles in the survival and pathogenicity of bacteria (46)(47)(48)(49). Our results revealed the perturbation of carbon metabolism (from glucose to cholesterol) on multiple PTMs, and further model structure analysis and MS experimentation suggested the potential for cross talk between these different PTMs (Fig.…”

Section: Discussionmentioning

confidence: 51%

Dynamic Characterization of Protein and Posttranslational Modification Levels in Mycobacterial Cholesterol Catabolism

Zhao

et al. 2020

mSystems

View full text Add to dashboard Cite

Cholesterol of the host macrophage membrane is vital for mycobacterial infection, replication, and persistence. During chronic infection within host lung tissues, cholesterol facilitates the phagocytosis of mycobacteria into macrophages. Cholesterol degradation leads to increased ﬂux of acetyl-coenzyme A (CoA) and propionyl-CoA, providing energy and building blocks for virulence macromolecules as well as donors for global protein acylation. Potential functions of lysine acylation are gradually revealed in bacterial survival and pathogenesis. However, the mycobacterial proteome and posttranslational modification (PTM) changes involved in the cholesterol catabolism bioprocess remain unclear. Here, we used nonpathogenic Mycobacterium smegmatis as a model and simultaneously monitored mycobacterial proteome and acetylome changes in the presence of glucose and cholesterol. We discovered that cholesterol metabolic enzymes were upregulated with respect to both protein expression levels and lysine acylation levels during the metabolic shift from glucose to cholesterol. After that, adenylating enzymes related to cholesterol metabolism were proven to be precisely regulated at the propionylation level by mycobacterial acyltransferase M. smegmatis Kat (MsKat) in response to cellular propionyl-CoA accumulation. Furthermore, the kinase expression and phosphorylation levels were also changed along with fluctuations in cholesterol levels. Our results expanded current knowledge of acylation regulation in the cholesterol catabolism of mycobacteria and provided references for possible antimycobacterium strategy. IMPORTANCE Cholesterol assimilation is a critical step in mycobacterial chronic infection. However, knowledge from the dynamic characterization of cholesterol metabolism in mycobacteria at the protein expression and PTM levels remains limited. Our study uncovered the landscape of protein expression, lysine acetylation, lysine propionylation, and S/T/Y phosphorylation during the metabolic changes from glucose to cholesterol in mycobacteria. The data showed that cholesterol-induced carbon shift resulted in the elevation of protein expression and lysine acylation in diverse metabolic enzymes involved in cholesterol degradation and that the presence of cholesterol also promoted the perturbations at the phosphorylation level in the kinase system in mycobacteria. This study systematically characterized the regulation of cholesterol catabolism at several different levels, which provided the detailed references in mycobacterial proteome and potential antimycobacterial strategies.

show abstract

A Lysine Acetyltransferase Contributes to the Metabolic Adaptation to Hypoxia in Mycobacterium tuberculosis

Cited by 40 publications

References 54 publications

Distinct Bacterial Pathways Influence the Efficacy of Antibiotics against Mycobacterium tuberculosis

Distinct Bacterial Pathways Influence the Efficacy of Antibiotics against Mycobacterium tuberculosis

Genome-wide identification of essential genes in Mycobacterium intracellulare by transposon sequencing — Implication for metabolic remodeling

Dynamic Characterization of Protein and Posttranslational Modification Levels in Mycobacterial Cholesterol Catabolism

Contact Info

Product

Resources

About