Curcumin
has been known to possess diverse pharmacological effects
at relatively nontoxic doses; however, its therapeutic potential is
severely restricted because of its low aqueous solubility and poor
stability under physiological conditions. To overcome its limitations,
we had previously designed several monocarbonyl curcuminoids by modifying
the central β-diketone moiety of curcumin. In this study, the
antibacterial activity of 33 curcuminoids from this designed library
has been screened, six of which displayed potent antibacterial activity
against clinically relevant Staphylococcus aureus. These curcuminoids were found to be very stable at physiological
conditions and did not cause any toxicity toward mammalian cells.
Mechanistically, out of these six curcuminoids, five caused instant
membrane depolarization and were able to permeabilize the bacterial
membrane, which could be the reason for their potent bactericidal
activity and the sixth one killed staphylococcal cells without damaging
the bacterial membrane. Overall, the present work established the
staphylocidal potency of six water-soluble, nontoxic curcuminoids,
thereby providing an impetus for the development of these lead curcuminoids
for therapeutic use against S. aureus.
Curcumin is an important molecule
with a plethora of pharmacological
activities and therapeutic potentials. Despite its efficacy, it remained
a potential drug candidate owing to hydrolytic instability and poor
aqueous solubility. To overcome the limitations related to low solubility,
low bioavailability, and the fact that curcumin is never present in
solution as a “single unit”, its complex was prepared
with Mn
II
with the idea that binding to a metal ion might
help to resolve these issues. The complex was characterized by elemental
and spectral analysis. The structure of the complex was determined
by density functional theory calculations. The complex was stable
at physiological buffer conditions, unlike curcumin. It did not have
any detrimental effect on mammalian cells. There was a significant
enhancement in the antibacterial activity of the complex compared
to curcumin against both Gram-positive (
Staphylococcus
aureus
) and Gram-negative (
Escherichia
coli
) bacteria. It showed a strong affinity for deoxyribonucleic
acid (DNA) evident from a high binding constant value with calf thymus
DNA and also from the retarded electrophoretic mobility of bacterial
plasmid DNA. The complex showed “superoxide dismutase-like”
activity leading to the generation of reactive oxygen species (ROS).
The complex caused bacterial membrane perturbation evident from calcein
leakage assay, which was further corroborated by scanning and transmission
electron microscopic experiments. Overall, the present study shows
improved stability and antibacterial potency of a nontoxic complex
over curcumin. Its multitargeting mode of action such as ROS-production,
effective binding with DNA, and permeabilization of bacterial membrane
together allows it to be an effective antibacterial agent that could
be taken further for therapeutic use against bacterial infections.
Staphylococcus aureus is an opportunistic pathogen, responsible for superficial and invasive infections both in nosocomial and community-acquired settings. The incidences of infection have become more problematic attributable to emerging drug resistance and biofilm formation. These challenges suggest the need for new antimicrobial agents against S. aureus. In present work, we purified a fungal xenobiotic (FI3) which elicits a potent antimicrobial activity against a list of tested microbes including methicillin sensitive (MSSA) and methicillin resistance (MRSA) S. aureus. The cell growth of MSSA and MRSA were completely ceased with the 1× minimum inhibitory concentration (MIC); 32 µg/mL and 128 µg/mL, respectively. The cell viability severely decreased within 90 min, due to disturbance of membrane homeostasis. This bactericidal effect was enhanced at lower pH (pH 4) with a speculation to retain positive charge. The FI3 potently disrupts biofilm adherence at 64 µg/mL and found to be a safe with no toxic effect on mammalian tissue. FI3 also leads to increase the potency of tested antibiotics. Taken together, we established that FI3 has a potent antimicrobial activity against tested microbes and safer to human tissue. It may be proven a leading molecule for the treatment of bacterial infections.
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