Killing persister cells and eradicating a biofilm infection by activating the ClpP protease

By Brian P. Conlon, Ernesto S. Nakayasu, Laura E. Fleck, Michael D. LaFleur, Vincent M. Isabella, K. Coleman, Steven N Leonard, Richard D. Smith, J. Adkins, Kim Lewis. Nature, 2013

626 citations recorded by the source corpus.

Chronic infections are difficult to treat with antibiotics but are caused primarily by drug-sensitive pathogens. Dormant persister cells that are tolerant to killing by antibiotics are responsible for this apparent paradox. Persisters are phenotypic variants of normal cells and pathways leading to dormancy are redundant, making it challenging to develop anti-persister compounds. Biofilms shield persisters from the immune system, suggesting that an antibiotic for treating a chronic infection should be able to eradicate the infection on its own. We reasoned that a compound capable of corrupting a target in dormant cells will kill persisters. The acyldepsipeptide antibiotic (ADEP4) has been shown to activate the ClpP protease, resulting in death of growing cells. Here we show that ADEP4-activated ClpP becomes a fairly nonspecific protease and kills persisters by degrading over 400 proteins, forcing cells to self-digest. Null mutants of clpP arise with high probability, but combining ADEP4 with rifampicin produced complete eradication of Staphylococcus aureus biofilms in vitro and in a mouse model of a chronic infection. Our findings indicate a general principle for killing dormant cells—activation and corruption of a target, rather than conventional inhibition. Eradication of a biofilm in an animal model by activating a protease suggests a realistic path towards developing therapies to treat chronic infections.

Subfields: Endocrinology, Genetics, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/c7517e982a861cec01705ba73f44667193738a32

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Citations in the corpus

Surviving as a community: antibiotic tolerance and persistence in bacterial biofilms (2019, positive): “aureus biofilms via activation of ClpP (Conlon et al., 2013).”
Biofilm-Related Infections: Bridging the Gap between Clinical Management and Fundamental Aspects of Recalcitrance toward Antibiotics (2014, background): “The activation of ClpP through ADEP4 results in the degradation of more than 400 proteins.”
Antibiotic resistance and persistence—Implications for human health and treatment perspectives (2020, positive): “The acyldeptipeptide ADEP4, for example, activates the protease ClpP in S. aureus , leading to non-specific and lethal protease activity (Conlon et al , 2013) (Fig 5B).”
Molecular mechanisms underlying bacterial persisters. (2014, neutral): “Staphylococcus aureus biofilms in vitro (Conlon et al., 2013).”
Staphylococcus aureus biofilms: recent developments in biofilm dispersal (2014, background): “The efficacy of dispersal-mediated treatments could potentially be improved by the inclusion of a drug targeting persister cells (Conlon et al., 2013).”
Mechanisms of bacterial persistence during stress and antibiotic exposure (2016, background): “ADEP4 can enforce activation of the ClpP protease by uncoupling it from the requirement to use ATP, thereby subverting ClpP protease activity to target a wide range of essential targets, such as ribosomal proteins (133).”