Photo: Hans S
Multidrug-resistant Gram-negative bacteria are a particular problem in both hospital and community settings and treatment is rendered more difficult by low intrinsic permeability to antibacterial compounds and by the presence of multidrug efflux pumps. The small number of molecular targets against which antibacterial compounds are directed is thought to have contributed to the emergence of multidrug-resistance but, despite much effort, only two new classes of antibiotics have reached the clinic in the past forty years. Connecting phenotype with mechanism in cell-based screening programmes has proved a significant challenge, but
scientists at McMaster University have used high copy suppression to determine the cellular targets of new antibacterial leads identified by high-throughput screening. In this approach, the abundance of an essential target at high copy is believed to exceed the amount of available compound, leading to a suppression of a growth-inhibitory phenotype. The team used an array of
E. coli clones over-expressing essential genes to screen for those that were able to suppress the activity of high-throughput screening actives.
MAC13243
As well as discovering new chemical genetic interactions for some known antibiotics, the team identified MAC13243, a new antibacterial compound that interferes with the bacterial lipoprotein targeting pathway. MAC13243 inhibits the function of LolA, a key component of this pathway, which is present in Gram-negative (but not Gram-positive) bacteria, and is the first compound that has been shown to act
via this mechanism.
Compound 19
A small array of tetrahydotriazines was then prepared to explore structure-activity relationships around MAC13243. Key findings were that a Cl- or Br-substituent in the
para-position of the thiobenzyl moiety is needed for good activity, and that potency is maintained if the dimethoxy-phenethyl group is truncated to a methyl group (Compound 19). Both MAC13243 and Compound 19 showed good activity against a number of Gram-negative bacteria, including clinical isolates, but had no impact on Gram-positive organisms, confirming their proposed mechanism of action. The effectiveness of MAC13243 was not impaired by over-expression of
acrB, which encodes the most pervasive multidrug efflux system, suggesting that the compound may represent an excellent starting point for the development of new treatments for infections caused by multidrug-resistant Gram-negative organisms.
The study is published in the journal Nature Chemical Biology.
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