The rapid growth of antibiotic resistance in Staphylococcus aureus coupled with their biofilm forming ability has made the infections difficult to treat with conventional antibiotics.
The
role of molecular arrangement of hydrophobic and hydrophilic
groups for designing membrane-active molecules remains largely ambiguous.
To explore this aspect, herein we report a series of membrane-active
small molecules by varying the spatial distribution of hydrophobic
groups. The two terminal amino groups of linear triamines such as
diethylene triamine, bis(trimethylene)triamine, and bis(hexamethylene)triamine
were conjugated with cationic amino acids bearing variable side chain
hydrophobicity (such as diaminobutyric acid, ornithine, and lysine).
The hydrophobicity was also modulated through conjugation of different
long chain fatty acids with the central secondary amino group of the
triamine. Molecules with constant backbone hydrophobicity displayed
an enhanced antibacterial activity and decreased hemolytic activity
upon increasing the side chain hydrophobicity of amino acids. On the
other hand, increased hydrophobicity in the backbone introduced a
slight hemolytic activity but a higher increment in antibacterial
activity, resulting in better selective antibacterial compounds. The
optimized lead compound derived from structure–activity-relationship
(SAR) studies was the dodecanoyl analogue of a lysine series of compounds
consisting of bis(hexamethylene)triamine as the backbone. This compound
was active against various Gram-positive and Gram-negative bacteria
at a low concentration (MIC ranged between 3.1 and 6.3 μg/mL)
and displayed low toxicity toward mammalian cells (HC50 = 890 μg/mL and EC50 against HEK = 85 μg/mL).
Additionally, it was able to kill metabolically inactive bacterial
cells and eradicate preformed biofilms of MRSA. This compound showed
excellent activity in a mouse model of skin infection with reduction
of ∼4 log MRSA burden at 40 mg/kg dose without any sign of
skin toxicity even at 200 mg/kg. More importantly, it revealed potent
efficacy in an ex vivo model of human skin infection (with reduction
of 85% MRSA burden at 50 μg/mL), which indicates great potential
of the compound as an antibacterial agent to treat skin infections.
Both histological and isoenzyme patterns of acid phosphatase were observed in callus tissue of Vigna unquiculate (L.) Walp. up to the tenth passage from its initiation. It was observed that when un-differentiated cells begin to transform into a differentiated condition in the form of tracheids, and xylem vessels, a new acid phosphatase band appears at the anionic end of the polyacrylamide gel. The transformation of living cells into a dead, empty tracheid during cellular differentiation and the biosynthesis of the acid phosphatase enzyme are functionally related to the autolysis of the cell contents and lignin synthesis.
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