c-di-AMP signaling plays important role in determining antibiotic tolerance phenotypes of Mycobacterium smegmatis

Pal, Aditya Kumar; Ghosh, Anirban

doi:10.1038/s41598-022-17051-z

Cited by 7 publications

(8 citation statements)

References 57 publications

(47 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Not all gdpP mutations found in clinical isolates conferred beta-lactam resistance, therefore the question remains whether those mutations might cause tolerance and thereby pave the way to resistance development (8,10). A role of c-di-AMP in multi-drug tolerance evolution has recently been proposed in Mycobacterium smegmatis (36). Our data suggest that increased c-di-AMP levels delay the ceftaroline effect by promoting tolerance, underlining the difficulties in eradicating these bacteria with certain antibiotics.…”

Section: Discussionmentioning

confidence: 76%

C-di-AMP levels modulateStaphylococcus aureuscell wall thickness as well as virulence and contribute to antibiotic resistance and tolerance

Haunreiter

Tarnutzer

Bär

et al. 2023

Preprint

View full text Add to dashboard Cite

Beta-lactam antibiotics are widely used to treat infections caused by the important human pathogen Staphylococcus aureus. Resistance to beta-lactams, as found in methicillin-resistant S. aureus (MRSA), renders effective treatment difficult. The second messenger cyclic di-3′,5′-adenosine monophosphate (c-di-AMP) promotes beta-lactam resistance in clinical S. aureus isolates. C-di-AMP plays a crucial role in the regulation of cellular processes such as virulence, cell wall homeostasis and resistance to beta-lactams in many bacterial species. In S. aureus, c-di-AMP synthesis is mediated by the diadenylate cyclase DacA, while its degradation is carried out by the phosphodiesterases GdpP and Pde2. In this work, we assessed the effect of altered c-di-AMP levels due to mutations in cacA, gdpP or gdpP/pde2 on virulence determinants. We report that a previously described growth defect in bacteria producing high c-di-AMP levels is mainly attributable to smaller cell size. High c-di-AMP levels also led to decreased survival upon oxidative stress, reduced production of the antioxidant staphyloxanthin, increased oxacillin and fosfomycin resistance and increased cell wall thickness. While resistance to ceftaroline was not affected, high c-di-AMP levels promoted tolerance to this antibiotic. In response to cell wall stress induced by antibiotics, the three-component regulatory system VraTSR mediates an increase in cell wall synthesis via the cell wall stress stimulon (CWSS). Increased c-di-AMP levels led to an activation of the CWSS. Upon deletion of vraR, resistance to oxacillin and fosfomycin as well as cell wall thickness diminished in the ΔgdpP mutant, indicating a contribution of the VraTSR system to the cell wall related phenotypes.

show abstract

Section: Discussionmentioning

confidence: 76%

C-di-AMP levels modulateStaphylococcus aureuscell wall thickness as well as virulence and contribute to antibiotic resistance and tolerance

Haunreiter

Tarnutzer

Bär

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…In all the kill kinetics and mutant detection assays, the initial inoculum was adjusted to ∼1 × 10 7 CFU/mL, which is based on the ciprofloxacin resistance frequency value of M. smegmatis WT, i.e., 4.5 × 10 –8 , to avoid any spontaneous mutant in the beginning of the assay.…”

Section: Resultsmentioning

confidence: 99%

“…The result suggests that the inhibition of regrowth of ciprofloxacin survived population and mutant enrichment at a lower concentration of the drug is only possible in the presence of selective isotetrone derivatives and not in the presence of vitamin C alone. In all the kill kinetics and mutant detection assays, the initial inoculum was adjusted to ∼1 × 10 7 CFU/mL, which is based on the ciprofloxacin resistance frequency value of M. smegmatis WT, i.e., 4.5 × 10 –8 , 63 to avoid any spontaneous mutant in the beginning of the assay.…”

Section: Resultsmentioning

confidence: 99%

C-4-Modified Isotetrones Prevent Biofilm Growth and Persister Cell Resuscitation in Mycobacterium smegmatis

et al. 2023

Self Cite

View full text Add to dashboard Cite

Hyperphosphorylated nucleotide (p)ppGpp, synthesized by Rel protein, regulates the stringent response pathway responsible for biofilm and persister cell growth in mycobacteria. The discovery of vitamin C as an inhibitor of Rel protein activities raises the prospect of tetrone lactones to prevent such pathways. The closely related isotetrone lactone derivatives are identified herein as inhibitors of the above processes in a mycobacterium. Synthesis and biochemical evaluations show that an isotetrone possessing phenyl substituent at C-4 inhibit the biofilm formation at 400 μg mL–1, 84 h post-exposure, followed by moderate inhibition by the isotetrone possessing the p-hydroxyphenyl substituent. The latter isotetrone inhibits the growth of persister cells at 400 μg mL–1 f.c. when monitored for 2 weeks, under PBS starvation. Isotetrones also potentiate the inhibition of antibiotic-tolerant regrowth of cells by ciprofloxacin (0.75 μg mL–1) and thus act as bioenhancers. Molecular dynamics studies show that isotetrone derivatives bind to the RelMsm protein more efficiently than vitamin C at a binding site possessing serine, threonine, lysine, and arginine.

show abstract

“…Rather, our data suggest that Δ disA is sensitive to aminoglycosides and marginally resistant to fluoroquinolone by diverse mechanisms (data not shown). Recently it was shown how the high c-di-AMP concentration mechanistically plays a role in antibiotic-resistant mutant generation in M. smegmatis , which again implicates the complex role of c-di-AMP messenger in the context of antibiotic resistance phenotypes in mycobacteria [ 52 ]. Finally, RNA-seq based transcriptome analysis revealed alternative gene expression profiles in null- and overproducing c-di-AMP mutants.…”

Section: Discussionmentioning

confidence: 99%

Elucidating the role of c-di-AMP in Mycobacterium smegmatis: Phenotypic characterization and functional analysis

Chaudhary

Pal

Singla

et al. 2023

Heliyon

Self Cite

View full text Add to dashboard Cite

c-di-AMP signaling plays important role in determining antibiotic tolerance phenotypes of Mycobacterium smegmatis

Cited by 7 publications

References 57 publications

C-di-AMP levels modulateStaphylococcus aureuscell wall thickness as well as virulence and contribute to antibiotic resistance and tolerance

C-di-AMP levels modulateStaphylococcus aureuscell wall thickness as well as virulence and contribute to antibiotic resistance and tolerance

C-4-Modified Isotetrones Prevent Biofilm Growth and Persister Cell Resuscitation in Mycobacterium smegmatis

Elucidating the role of c-di-AMP in Mycobacterium smegmatis: Phenotypic characterization and functional analysis

Contact Info

Product

Resources

About