Publication Date:
2013-11-15
Description:
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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4031760/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4031760/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Conlon, B P -- Nakayasu, E S -- Fleck, L E -- LaFleur, M D -- Isabella, V M -- Coleman, K -- Leonard, S N -- Smith, R D -- Adkins, J N -- Lewis, K -- P41 GM103493/GM/NIGMS NIH HHS/ -- P41 GM103493-11/GM/NIGMS NIH HHS/ -- R01 AI085585/AI/NIAID NIH HHS/ -- T-R01AI085585/AI/NIAID NIH HHS/ -- Y1-AI-8401/AI/NIAID NIH HHS/ -- England -- Nature. 2013 Nov 21;503(7476):365-70. doi: 10.1038/nature12790. Epub 2013 Nov 13.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Antimicrobial Discovery Center, Department of Biology, Northeastern University, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24226776" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
Anti-Bacterial Agents/*pharmacology
;
Bacterial Proteins/metabolism
;
Biofilms/*drug effects/*growth & development
;
Depsipeptides/pharmacology
;
Drug Resistance, Bacterial/drug effects
;
Enzyme Activation/drug effects
;
Female
;
Mice
;
Microbial Viability/drug effects
;
Proteolysis/*drug effects
;
Proteomics
;
Rifampin/pharmacology
;
Serine Endopeptidases/*metabolism
;
Staphylococcal Infections/drug therapy/microbiology
;
Staphylococcus aureus/classification/*drug effects/*enzymology/metabolism
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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