3 research outputs found
Pyrazolopyrimidines Establish MurC as a Vulnerable Target in <i>Pseudomonas aeruginosa</i> and <i>Escherichia coli</i>
The bacterial peptidoglycan biosynthesis
pathway provides multiple
targets for antibacterials, as proven by the clinical success of β-lactam
and glycopeptide classes of antibiotics. The Mur ligases play an essential
role in the biosynthesis of the peptidoglycan building block, <i>N</i>-acetyl-muramic acid-pentapeptide. MurC, the first of four
Mur ligases, ligates l-alanine to UDP-<i>N</i>-acetylmuramic
acid, initiating the synthesis of pentapeptide precursor. Therefore,
inhibiting the MurC enzyme should result in bacterial cell death.
Herein, we report a novel class of pyrazolopyrimidines with subnanomolar
potency against both <i>Escherichia coli</i> and <i>Pseudomonas aeruginosa</i> MurC enzymes, which demonstrates
a concomitant bactericidal activity against efflux-deficient strains.
Radio-labeled precursor incorporation showed these compounds selectively
inhibited peptidoglycan biosynthesis, and genetic studies confirmed
the target of pyrazolopyrimidines to be MurC. In the presence of permeability
enhancers such as colistin, pyrazolopyrimidines exhibited low micromolar
MIC against the wild-type bacteria, thereby, indicating permeability
and efflux as major challenges for this chemical series. Our studies
provide biochemical and genetic evidence to support the essentiality
of MurC and serve to validate the attractiveness of target for antibacterial
discovery
Discovery of Imidazo[1,2‑<i>a</i>]pyridine Ethers and Squaramides as Selective and Potent Inhibitors of Mycobacterial Adenosine Triphosphate (ATP) Synthesis
The approval of bedaquiline
to treat tuberculosis has validated
adenosine triphosphate (ATP) synthase as an attractive target to kill Mycobacterium tuberculosis (Mtb). Herein, we report
the discovery of two diverse lead series imidazoÂ[1,2-<i>a</i>]Âpyridine ethers (IPE) and squaramides (SQA) as inhibitors of mycobacterial
ATP synthesis. Through medicinal chemistry exploration, we established
a robust structure–activity relationship of these two scaffolds,
resulting in nanomolar potencies in an ATP synthesis inhibition assay.
A biochemical deconvolution cascade suggested cytochrome c oxidase
as the potential target of IPE class of molecules, whereas characterization
of spontaneous resistant mutants of SQAs unambiguously identified
ATP synthase as its molecular target. Absence of cross resistance
against bedaquiline resistant mutants suggested a different binding
site for SQAs on ATP synthase. Furthermore, SQAs were found to be
noncytotoxic and demonstrated efficacy in a mouse model of tuberculosis
infection
Discovery of Imidazo[1,2‑<i>a</i>]pyridine Ethers and Squaramides as Selective and Potent Inhibitors of Mycobacterial Adenosine Triphosphate (ATP) Synthesis
The approval of bedaquiline
to treat tuberculosis has validated
adenosine triphosphate (ATP) synthase as an attractive target to kill Mycobacterium tuberculosis (Mtb). Herein, we report
the discovery of two diverse lead series imidazoÂ[1,2-<i>a</i>]Âpyridine ethers (IPE) and squaramides (SQA) as inhibitors of mycobacterial
ATP synthesis. Through medicinal chemistry exploration, we established
a robust structure–activity relationship of these two scaffolds,
resulting in nanomolar potencies in an ATP synthesis inhibition assay.
A biochemical deconvolution cascade suggested cytochrome c oxidase
as the potential target of IPE class of molecules, whereas characterization
of spontaneous resistant mutants of SQAs unambiguously identified
ATP synthase as its molecular target. Absence of cross resistance
against bedaquiline resistant mutants suggested a different binding
site for SQAs on ATP synthase. Furthermore, SQAs were found to be
noncytotoxic and demonstrated efficacy in a mouse model of tuberculosis
infection