Inhibiting Bacterial Signalling Reduces Virulence

bacteriaQuorum sensing is used by bacteria to coordinate gene expression according to local population densities. The bacteria secrete signalling molecules and have receptors that can specifically recognize signalling molecules released by other bacteria of the same or different species. When the concentration of the signalling molecule reaches a certain concentration (i.e. many bacteria in the location), a response is triggered.

In 2006, researchers at UT Southwestern Medical Center described how blocking a newly discovered receptor in a strain of E. Coli could prevent infection. When contaminated food containing a virulent strain of E. Coli is eaten, the bacteria cause no damage until they encounter signalling molecules produced by native gut flora together with the human hormones, adrenaline and noradrenaline. These molecular signals prompt the virulent E.Coli bacteria to release enterotoxins which, in extreme cases, can be fatal.

In a recent report in the journal Science, Dr Sperandio’s group now describe the activity of a small molecule, LED209, which doesn’t inhibit bacterial growth but which markedly inhibits the virulence of several bacterial strains, both in vitro and in infected animals.
Many bacterial pathogens rely on signalling pathways using the same “adrenergic-type” receptor to promote the expression of virulence factors, so inhibition of this pathway may offer a strategy for the development of new broad-spectrum antimicrobial drugs. It is also possible that antagonists of this signalling pathway may not give rise to the widespread resistance seen with traditional antimicrobial agents.

Progress in Targeting the Sliding Clamp

There has been interest in the DNA polymerase sliding clamp as an antibacterial target for the last 15 years. Sliding clamp proteins, found in all organisms, encircle DNA (and slide along it!) and tether polymerases to enable rapid and processive DNA replication. The proteins are known as proliferating cell nuclear antigen (PCNA) in eukaryotes and as the β-clamp in prokaryotes. In PCNA the clamp is composed of three subunits of two domains each, whilst the bacterial β-clamp is assembled from two subunits of three domains. Although the overall structures of the eukaryotic and prokaryotic clamps are similar, there is no detectable sequence homology.

RU7In a paper to be published in the August 12th edition of PNAS, the authors disclose a small molecule inhibitor of the E.coli β-clamp, RU7, which differentially inhibits polymerases II, III and IV.

RU7 selectively inhibits Pol III in β-dependent replication assays, with no activity in the eukaryotic PCNA system. The compound, which has modest potency, was identified by screening for compounds able to displace a Pol III peptide from the β-clamp. The authors have also determined the co-crystal structure of RU7 bound to the clamp (pdb identifier 3d1g), paving the way for structure-based design.