Relacin - a novel antibacterial targeting the stringent response, maybe

The stringent response is a promising target for novel antibacterials: it is involved in virulence and antibiotic insensitivity, and inhibiting the stringent response would disarm the bug, making is both less evil and easier to kill.

A new study is came out in PLoS Pathogens describing a novel Rel inhibitor, relacin (Fig. 1). Wexselblatt and colleagues are following up their earlier work on derivatizing ppGpp into a Rel inhibitor  and are now testing the compound not only in vitro, but also in vivo.

Fig 1: the chemical structure of relacin.

They show that relacin efficiently inhibits sporulation of Bacillus subtilis. Sporulation in this organism is driven by ppGpp, and inhibitory effect of relacin is a strong indication that it actually works. However, really high concentrations are needed to achieve significant effects: 0.5 - 2 mM. At these concentrations one would expect that in addition to hitting RelA, relacin will affect all the other ppGpp targets, i.e. translational GTPases, GTP biosynthesis enzymes etc. The authors do not test these effects. It would be easy to do it in an in vitro translational lysate... but, unfortunately, this is not done.  By using a GFP-fusion reporter, they do show that relacin inhibits translation of mid-sporulation protein SpoIIQ, but they do not check that it does not inhibit translation in general. A simple test of GFP expression would do.

With this (potential) absence of specificity relacin is unlikely to be the 'magic bullet' inhibiting just the stringent response and making bacterial less pathogenic, but still viable. However, relacin is just the first step. There is a hope that the derivatives to come will work at more in vivo-relevant concentrations and will be highly Rel-specific.

References:

Wexselblatt et al. Biomed Org Chem (2010) PIMD: 20483622

Wexselblatt et al. PLoS Pathogens (2012)