Dataset Information

Phenol-Soluble Modulins Modulate Persister Cell Formation in Staphylococcus aureus.

ABSTRACT: Staphylococcus aureus is a human pathogen that can cause chronic and recurrent infections and is recalcitrant to antibiotic chemotherapy. This trait is partly attributed to its ability to form persister cells, which are subpopulations of cells that are tolerant to lethal concentrations of antibiotics. Recently, we showed that the phenol-soluble modulins (PSMs) expressed by S. aureus reduce persister cell formation. PSMs are a versatile group of toxins that, in addition to toxicity, form amyloid-like fibrils thought to support biofilm structures. Here, we examined individual or combined synthetic PSM? peptides and their equivalent amyloid-like fibrils on ciprofloxacin-selected S. aureus persister cells. We found that PSM?2 and the mixture of all four alpha peptides consistently were able to reduce persister frequency in all growth phases, and this activity was specifically linked to the presence of the soluble peptide as no effect was seen with fibrillated peptides. Persister reduction was particularly striking in a mutant that, due to mutations in the Krebs cycle, has enhanced ability to form persisters with PSM?4 and the combination of peptides being most effective. In biofilms, only the combination of peptides displayed persister reducing activity. Collectively, we report the individual contributions of PSM? peptides to persister cell reduction and that the combination of peptides generally was most effective. Strikingly, the fibrillated peptides lost activity and thus, if formed in bacterial cultures, they will be inactive against persister cells. Further studies will be needed to address the biological role of phenol-soluble modulins in reducing persister cells.

SUBMITTER: Baldry M

PROVIDER: S-EPMC7680730 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Phenol-Soluble Modulins Modulate Persister Cell Formation in Staphylococcus aureus.

Baldry Mara M Bojer Martin S MS Najarzadeh Zahra Z Vestergaard Martin M Meyer Rikke Louise RL Otzen Daniel Erik DE Ingmer Hanne H

Frontiers in microbiology 20201109

Staphylococcus aureus is a human pathogen that can cause chronic and recurrent infections and is recalcitrant to antibiotic chemotherapy. This trait is partly attributed to its ability to form persister cells, which are subpopulations of cells that are tolerant to lethal concentrations of antibiotics. Recently, we showed that the phenol-soluble modulins (PSMs) expressed by S. aureus reduce persister cell formation. PSMs are a versatile group of toxins that, in addition to toxicity, ...[more]

PMID: 33240231

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Project description:Incomplete killing of bacterial pathogens by antibiotics is an underlying cause of treatment failure and accompanying complications. Among those avoiding chemotherapy are persisters being individual cells in a population that for extended periods of time survive high antibiotic concentrations proposedly by being in a quiescent state refractory to antibiotic killing. While investigating the human pathogen Staphylococcus aureus and the influence of growth phase on persister formation, we noted that spent supernatants of stationary phase cultures of S. aureus or S. epidermidis, but not of distantly related bacteria, significantly reduced the persister cell frequency upon ciprofloxacin challenge when added to exponentially growing and stationary phase S. aureus cells. Curiously, the persister reducing activity of S. aureus supernatants was also effective against persisters formed by either S. carnosus or Listeria monocytogenes. The persister reducing component, which resisted heat but not proteases and was produced in the late growth phase in an agr quorum-sensing dependent manner, was identified to be the phenol-soluble modulin (PSM) toxins. S. aureus express several PSMs, each with distinct cytolytic and antimicrobial properties; however, the persister reducing activity was specifically linked to synthesis of the PSMα family. Correspondingly, a high-persister phenotype of a PSMα mutant was observed upon fluoroquinolone or aminoglycoside challenge, demonstrating that the persister reducing activity of PSMs can be endogenously synthesized or extrinsically added. Given that PSMs have been associated with lytic activity against bacterial membranes we propose that PSM toxins increase the susceptibility of persister cells to killing by intracellularly acting antibiotics and that chronic and re-occurring infections with quorum sensing, agr negative mutants may be difficult to treat with antibiotics because of persister cells formed in the absence of PSM toxins.

Dataset Information

Phenol-Soluble Modulins Modulate Persister Cell Formation in Staphylococcus aureus.

Publications

Phenol-Soluble Modulins Modulate Persister Cell Formation in <i>Staphylococcus aureus</i>.

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