2 research outputs found
Development of Novel Membrane Disrupting Lipoguanidine Compounds Sensitizing Gram-Negative Bacteria to Antibiotics
A new class of amphiphilic
molecules, the lipoguanidines, designed
as hybrids of guanidine and fatty acid compounds, has been synthesized
and developed. The new molecules present both a guanidine polar head
and a lipophilic tail that allow them to disrupt bacterial membranes
and to sensitize Gram-negative bacteria to the action of the narrow-spectrum
antibiotics rifampicin and novobiocin. The lipoguanidine 5g sensitizes Klebsiella pneumonia, Acinetobacter
baumannii, Pseudomonas aeruginosa, and Escherichia coli to rifampicin, thereby reducing the antibiotic
minimum inhibitory concentrations (MIC) up to 256-fold. Similarly, 5g is able to potentiate novobiocin up to 64-fold, thereby
showing a broad spectrum of antibiotic potentiating activity. Toxicity
and mechanism studies revealed the potential of 5g to
work synergistically with rifampicin through the disruption of bacterial
membranes without affecting eukaryotic cells
Insights into the Spectrum of Activity and Mechanism of Action of MGB-BP‑3
MGB-BP-3
is a potential first-in-class antibiotic, a Strathclyde
Minor Groove Binder (S-MGB), that has successfully completed Phase
IIa clinical trials for the treatment of Clostridioides
difficile associated disease. Its precise mechanism
of action and the origin of limited activity against Gram-negative
pathogens are relatively unknown. Herein, treatment with MGB-BP-3
alone significantly inhibited the bacterial growth of the Gram-positive,
but not Gram-negative, bacteria as expected. Synergy assays revealed
that inefficient intracellular accumulation, through both permeation
and efflux, is the likely reason for lack of Gram-negative activity.
MGB-BP-3 has strong interactions with its intracellular target, DNA,
in both Gram-negative and Gram-positive bacteria, revealed through
ultraviolet–visible (UV–vis) thermal melting and fluorescence
intercalator displacement assays. MGB-BP-3 was confirmed to bind to
dsDNA as a dimer using nano-electrospray ionization mass spectrometry
and nuclear magnetic resonance (NMR) spectroscopy. Type II bacterial
topoisomerase inhibition assays revealed that MGB-BP-3 was able to
interfere with the supercoiling action of gyrase and the relaxation
and decatenation actions of topoisomerase IV of both Staphylococcus aureus and Escherichia
coli. However, no evidence of stabilization of the
cleavage complexes was observed, such as for fluoroquinolones, confirmed
by a lack of induction of DSBs and the SOS response in E. coli reporter strains. These results highlight
additional mechanisms of action of MGB-BP-3, including interference
of the action of type II bacterial topoisomerases. While MGB-BP-3′s
lack of Gram-negative activity was confirmed, and an understanding
of this presented, the recognition that MGB-BP-3 can target DNA of
Gram-negative organisms will enable further iterations of design to
achieve a Gram-negative active S-MGB