2‑Aminoimidazole Analogs Target PhoP Altering DNA Binding Activity and Affect Outer Membrane Stability in Gram-Negative Bacteria

Multidrug-resistant bacteria cause immense public health
concerns
as once effective antibiotics no longer work against even common infections.
Concomitantly, there has been a decline in the discovery of new antibiotics,
and the current global clinical pipeline is woefully inadequate, especially
against resistant Gram-negative bacteria. One major contribution to
Gram-negative resistance is the presence of a protective outer membrane.
Consequently, an appealing option for tackling resistance is to adversely
affect that outer membrane. With that in mind, we define the response
regulator PhoP as a target for new 2-aminoimidazole compounds and
show that they affect the integrity of the outer membrane in resistant
strains of Escherichia coli and Klebsiella
pneumoniae. We also provide empirical evidence for the 2-aminoimidazole
mechanism of action.