Editors' ChoiceInfectious Disease

ADEP Leaves No Survivors

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Science Translational Medicine  18 Dec 2013:
Vol. 5, Issue 216, pp. 216ec210
DOI: 10.1126/scitranslmed.3008135

Chronic bacterial infections, such as endocarditis, osteomyelitis, and catheter infections, can be difficult to eradicate with antibiotics. This phenomenon is primarily due to the presence of bacterial biofilms, which are aggregates of dormant bacteria that adhere to surfaces and are tolerant to the effects of antibiotics. These “persisters,” although not genetically resistant to antibiotics, are able to avoid the effects of antibiotics because of their dormancy—antibiotics usually target pathways that are not in use in dormant cells.

A new class of compounds, known as acyldepsipeptides (ADEPs), act by turning on a bacterial protein called ClpP, which normally breaks down proteins that are not formed properly. In the presence of ADEPs, ClpP remains activated and nonspecifically breaks down proteins, resulting in bacterial killing. Conlon and colleagues sought to determine whether one member of this antibiotic family, ADEP4, could cause protein breakdown even in dormant cells. The authors first compared proteins from stationary (nondividing) Staphylococcus aureus bacteria that were treated versus not treated with ADEP4. They found that ADEP4 treatment resulted in breakdown of over 400 bacterial proteins with varying functions. Next, to determine whether ADEP4 could kill persister cells, the authors examined a culture of stationary S. aureus that could not be killed with conventional antibiotics and found a 4 log10 decrease in cell counts with ADEP4 treatment. The bacterial cells rebounded 3 days after treatment because of the development of mutations in ClpP that made the bacteria resistant to ADEP4. However, when ADEP4 was combined with conventional antibiotics, the stationary S. aureus was eradicated. Similar results were obtained by using S. aureus biofilms from an osteomyelitis-associated strain. Last, using a mouse model of a chronic S. aureus infection of the thigh that could not be cured with conventional antibiotics, the authors showed that ADEP4 combined with the antibiotic rifampicin led to sterilization of the infected tissue within 24 hours.

This study demonstrates that a new class of antibiotics that activates protein breakdown can kill stationary bacteria and persister bacteria in biofilms in culture and in a mouse model. Importantly, the study demonstrates that this class of compounds can perform their action even in dormant, nongrowing bacterial cells. Targeting pathways that are present in dormant cells, including other protein breakdown pathways, may provide a much-needed future treatment option for chronic bacterial infections due to biofilms.

B. P. Conlon et al., Activated ClpP kills persisters and eradicates a chronic biofilm infection. Nature 503, 365–370 (2013). [Abstract]

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