Monday, August 20, 2018

BacterioFiles 352 - Staphylococcus Stops Skin Swellings

Staphylococcus epidermidis
This episode: A harmless strain of bacteria on the skin produces a compound that can prevent tumors from forming!

Download Episode (9.2 MB, 10 minutes)

Show notes:
Microbe of the episode: Hamiltonella virus APSE1

News item

Journal Paper:
Nakatsuji T, Chen TH, Butcher AM, Trzoss LL, Nam S-J, Shirakawa KT, Zhou W, Oh J, Otto M, Fenical W, Gallo RL. 2018. A commensal strain of Staphylococcus epidermidis protects against skin neoplasia. Sci Adv 4:eaao4502.

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Episode outline:
  • Background: Microbiota important for most parts of body, function of immune system
    • Gut but also skin and others
  • Help defend against pathogens like Staphylococcus aureus
  • Can also help regulate inflammation after injury
  • What’s new: Now, scientists publishing in Science Advances have discovered another useful function of skin microbes—protecting against cancer!
  • Methods: Were testing strains of Staphylococcus that live on healthy skin for antimicrobials
    • Found one S. epidermidis that can secrete inhibitor of Streptococcus pathogens
    • Purified and identified as a small molecule, not a protein: 6-N-hydroxyaminopurine
      • Or 6-HAP
    • Synthesized specifically by the bacteria, not byproduct of metabolism
  • 6-HAP similar in structure to nucleic acid base, adenine, or A of AGCT
    • Might interact with DNA/RNA metabolism somehow
    • So tested with DNA polymerase
      • 6-HAP inhibited DNA synthesis when addition of adenine nucleotide required
    • So can prevent DNA synthesis and therefore can prevent cell replication/proliferation
  • Possibly useful against cancer, since it proliferates much more than normal skin cells?
    • Tested against several cancer lines and normal cells with BrdU
      • fluorescent tag similar to thymine, shows DNA synthesis
    • 6-HAP prevented cancer lines from incorporating it (and thus making DNA)
      • But didn't prevent normal cells
  • Why the selectiveness? Mediated by mARCs
    • Mitochondrial amidoxime reducing components – convert stuff like 6-HAP to normal bases
    • More activity in normal cells than cancer
    • When inhibited in normal, reduced resistance to 6-HAP to be more like cancer cells
  • Still, important to ensure 6-HAP doesn't interfere with DNA; could cause mutations
    • Tested with a couple mutagenesis tests, in mouse cells and bacteria
    • But found no mutagenic activity
  • Then actually tested in a live context - in mice with tumors
    • In healthy mice, 6-HAP alone didn't show toxicity even at max dose for 2 weeks injected
    • So then gave to mice inoculated with melanoma cell line to induce tumors
    • Despite aggressive tumors, size suppressed by >60%
  • So molecule works, but what about bacteria that make it?
    • Induced tumors on mouse skin with UV+carcinogen
    • And colonized mouse skin with S. epidermidis, either producing 6-HAP or not
    • Producers had fewer tumors, non-producers had normal number
  • Finally looked in human microbiome datasets, found 6-HAP producers common in humans
  • Summary: Healthy skin bacteria produce compound with antitumor properties, could help prevent skin cancer
  • Applications and implications: Maybe new treatment for cancer
    • Or basis for developing one
  • Useful for research too, when selectively inhibiting DNA synthesis is desired
  • Clarifications if necessary: Seems like resistance could evolve fairly easily
    • Seems already present in healthy cells, in enzymes that degrade 6-HAP
    • So just need for cancer not to inactivate enzymes; not so hard?
  • What do I think: Shows importance of healthy microbiota, even on skin
    • Some evidence that disruptions increase risk of cancer, at least in gut
    • This anticancer molecule production could contribute to effect
    • In addition to immune modulation
    • And maybe disruption of other microbes that increase risks
  • Need to understand better

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