by ecancer reporter Janet Fricker

A new approach using an emerging class of antibiotics - acyldepsipetides (ADEP4) - to treat persistent infections has been highlighted in a study published in Nature.

The current antibiotics crisis stems from two distinct phenomenons - drug resistance and drug tolerance.

While drug resistance includes mechanisms such as drug efflux, tolerance is a property of persister cells.

Although first discovered in 1944 by Joseph Bigger, it was only recently that persisters have been recognised as rare, slow-growing, bacterial cells that are genetically identical to the rest of the population.

Since most existing antibiotics target rapidly growing bacteria, persisters manage to escape. They typically occur at a frequency of one in 10,000 to one in a million cells.

Structural studies have revealed that ADEPs bind directly to ClpP proteases, enzyme found in all bacteria that have protein-quality control functions.

Binding increases the size of the ClpP central pore providing unregulated access for peptides and proteins to the proteolytic chamber resulting in protein degradation and cell death.

In the current study Kim Lewis and colleagues, from Northeastern University, Boston, MA, reasoned that a compound capable of corrupting a target in dormant energy-deprived cells would be capable of killing persisters.

First the team showed that ADEP4 efficiently killed non-growing, stationary-phase bacteria.

Next they showed that in combination with conventional antibiotics (rifampicin, linezolid or ciprofloxacin) that does not kill persisters when administered alone, ADEP4 totally eradicated persisters from a flask culture, from a biofilm (a distinct form of aggregated bacteria growing on surfaces such as catheters, prostheses and heart valves) and from an in vitro hollow-fibre model used for assessing the efficacy of antibiotics.

Most strikingly, the authors found that ADEP4 eradicated severe, deep-seated S. aureus infections in the thighs of mice.

“This study shows that persisters are not invulnerable, and helps settle an important uncertainty surrounding chronic diseases—it has been unclear whether conventional antibiotics fail owing to their ineffective killing or simply because they do not reach all pathogens at the site of infection,” write the authors.

Apart from ADEP4, they add, other activators of CLpP may be developed into therapeutics, and additional bacterial proteases such as Lon could be used as targets for killing specialized survivor cells.

“This general principle of killing may be applied to other organisms as well and prove effective in developing therapeutics to treat fungal infections and cancer.

In an accompanying news and views piece, Kenn Gerdes, from Newcastle University and Hanne Ingmer, from University of Copenhagen, write, ‘This growing body of results generates hope that antibiotics for the treatment of persistent infections will be available in the future.’

A key question that remains is whether bacteria will develop resistance to ADEPs.

“Bacteria almost always rapidly become resistant to new anti¬biotics, so it is to be expected that this will also be the case with ADEPs.

But general proteases such as Clp are typically either essential for bacterial survival or are required for bacterial virulence.

Therefore, if spontaneous S. aureus mutants arise that lack ClpP and are resistant to ADEPs, they will display greatly reduced virulence,” write the authors.

Reference

B Conlon, E Nakayasu, L Fleck, et al. Activated ClpP kills persisters and eradicates a chronic biofilm infection. Nature. doi:10.1038/nature12790

K Gerdes, H Ingmer. News&Views. Killing the survivors. doi:10.1038/nature12834