The world is understandably
focused on SARS-CoV-2; see for example last week’s post. But there are many
other threats out there, including infectious Pseudomonas aeruginosa, which
is particularly problematic for immunocompromised people. A recent (open
access!) ChemMedChem paper by Martin Empting and collaborators at the
Helmholtz Centre for Infection Research and elsewhere describes a clever
approach to tackle this pathogen.
An age-old problem for
antibiotics is that they provoke resistance: nothing like death to kick
evolution into high gear. One way to sidestep this is to develop drugs that
target virulence rather than essential microbial pathways. The protein PqsR is
part of the Pseudomonas Quinolone Signal Quorum Sensing system, and is
important for pathogenicity.
A previously published screen of
720 fragments by SPR yielded about 40 hits, including compound 3. Not only does
this compound have impressive ligand efficiency, it also has high enthalpic efficiency; the binding is largely enthalpy-driven. Although the utility of
thermodynamics for lead optimization is questionable, the researchers were
cognizant of the hydrophobic nature of the ligand binding site for PqsR, and
sought molecules that would make polar interactions from the start rather than
having to engineer them; a similar strategy proved successful for Astex.
Crystallography with compound 3 was
unsuccessful, but SAR by catalog led to compound 7, which has higher affinity
for PqsR as assessed by isothermal titration calorimetry (ITC) and also shows activity
in a reporter gene assay. Fragment growing led to compound 11, which the
researchers were able to characterize crystallographically. The two aromatic
rings are at a sharp angle to one another, and attempts at rigidifying the
linker proved unsuccessful. But further growing led to compound 20, with
submicromolar activity in the reporter assay. This molecule also reduced
release of a toxic virulence factor from a clinical isolate of P. aeruginosa.
Interestingly, despite the
increased activity of compound 20 over compound 11 in the reporter assay, it
seems to have lower affinity for PqsR by ITC. The researchers suggest that the
full protein in cells likely behaves differently than the truncated version
studied in the biophysical assays.
The researchers also emphasize
that flexible linkers were more successful than rigid linkers in improving
potency – a phenomenon we’ve previously highlighted here and here. Intuitively a more
flexible linker is likely to be more forgiving, as a fraction of an ångström
can make the difference between binding or not.
There is still much to do: in
particular, activity will need to be improved further, and no pharmacokinetic or
other animal data are provided. Moreover, a clinical trial with an anti-virulence
strategy would be difficult to design. Still, this is an interesting approach,
and I hope the authors or others will follow up on it.
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