New Broad-Spectrum Peptide Antibiotic Targets Biofilms

Biofilm Biofilms are structured multicellular communities of microorganisms associated with surfaces. They have been widely studied, in part because they cause at least 65% of all human infections, being particularly prevalent in device-related infections, on body surfaces and in chronic infections. Biofilms represent a major health problem worldwide due to their resistance to host defence mechanisms and to conventional antimicrobials, which generally target free-swimming (planktonic) bacteria. So there is an urgent need to identify compounds that effectively clear biofilm-related infections.

A new report in PLoS Pathogens identifies a potent anti-biofilm peptide that works by blocking (p)ppGpp, an important signal in biofilm development. The peptide had at least three effects on biofilms, which might reflect the role of (p)ppGpp in cells. First when added prior to initiation of biofilms it prevented biofilm formation, second it specifically led to cell death in biofilms at concentrations that were not lethal for planktonic (free-swimming) cells, and third it promoted biofilm dispersal even in maturing (2-day old) biofilms. This anti-biofilm strategy represents a significant advance in the search for new agents that specifically target many bacterial species.

 

Broad-Spectrum Anti-biofilm Peptide That Targets a Cellular Stress Response. (2014) PLoS Pathog 10(5): e1004152. doi:10.1371/journal.ppat.1004152
Bacteria form multicellular communities known as biofilms that cause two thirds of all infections and demonstrate a 10 to 1000 fold increase in adaptive resistance to conventional antibiotics. Currently, there are no approved drugs that specifically target bacterial biofilms. Here we identified a potent anti-biofilm peptide 1018 that worked by blocking (p)ppGpp, an important signal in biofilm development. At concentrations that did not affect planktonic growth, peptide treatment completely prevented biofilm formation and led to the eradication of mature biofilms in representative strains of both Gram-negative and Gram-positive bacterial pathogens including Pseudomonas aeruginosa, Escherichia coli, Acinetobacter baumannii, Klebsiella pneumoniae, methicillin resistant Staphylococcus aureus, Salmonella Typhimurium and Burkholderia cenocepacia. Low levels of the peptide led to biofilm dispersal, while higher doses triggered biofilm cell death. We hypothesized that the peptide acted to inhibit a common stress response in target species, and that the stringent response, mediating (p)ppGpp synthesis through the enzymes RelA and SpoT, was targeted. Consistent with this, increasing (p)ppGpp synthesis by addition of serine hydroxamate or over-expression of relA led to reduced susceptibility to the peptide. Furthermore, relA and spoT mutations blocking production of (p)ppGpp replicated the effects of the peptide, leading to a reduction of biofilm formation in the four tested target species. Also, eliminating (p)ppGpp expression after two days of biofilm growth by removal of arabinose from a strain expressing relA behind an arabinose-inducible promoter, reciprocated the effect of peptide added at the same time, leading to loss of biofilm. NMR and chromatography studies showed that the peptide acted on cells to cause degradation of (p)ppGpp within 30 minutes, and in vitro directly interacted with ppGpp. We thus propose that 1018 targets (p)ppGpp and marks it for degradation in cells. Targeting (p)ppGpp represents a new approach against biofilm-related drug resistance.

 

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One Response to New Broad-Spectrum Peptide Antibiotic Targets Biofilms

  1. Ron Huber says:

    Dear Microbiologybytes

    Your article noted that a new broad spectrum peptide antibiotic appears to be effective in preventing biofilm formation and breaking up those already formed. Wonderful and a tremendous tool for medicine. But when you observe that:

    “Biofilms are structured multicellular communities of microorganisms associated with surfaces. They have been widely studied, in part because they cause at least 65% of all human infections, being particularly prevalent in device-related infections, on body surfaces and in chronic infections.”

    You need also observe

    “…Biofilms are structured multicellular communities of microorganisms associated with surfaces. They have been widely studied, in part because they are involved in facilitating nearly every marine invertebrate species’ survival at one life stage or another, and are particularly prevalent in estuarine and other coastal waters, on nearly every other marine surface and in ecological choke points where their absence spells doom for shellfish larvae whose grazing species is absent, because the biofilm that their food organisms would set up upon would not be there.”

    Of concern to us as bay conservationists is whether these broad spectrum peptide antibiotics are digested by standard sewage treatment plant technology or pass essentially unscathed through the patient and the wastewater treatment facility and into the receiving waters. We want and absolutely need vigorous marine biofilms, an at a variety of scales and species mixes, if we are to have mussels, lobsters, clams, oysters and other organisms at all.

    Is the antibiotic broadspectrum enough to impact sea scallops symbiotic biofilms on gills and in gut?
    Is it robust and still effective post outfall discharge?
    If so, how can we use this new (and critically needed) broad spectrum biofilm buster medically in coastal Maine, _without_ impacting the “good biofilms” of Penobscot Bay beyond the sewage treatment plants’ outfalls? Not to mention the myriad coasts of “Away”.

    Sewage plants are adaptable; can something be added that would bind with the antibiotic or otherwise render it harmless before discharge?
    We would really like to know!
    Best
    Ron Huber
    Friends of Penobscot Bay

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