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Systematic Study of Non‐Natural Short Cationic Lipopeptides as Novel Broad‐Spectrum Antimicrobial Agents
Author(s) -
Lohan Sandeep,
Cameotra Swaranjit S.,
Bisht Gopal S.
Publication year - 2013
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/cbdd.12182
Subject(s) - lipopeptide , antimicrobial , surfactin , microbiology and biotechnology , staphylococcus epidermidis , chemistry , staphylococcus aureus , bacteria , broad spectrum , antibiotics , biology , combinatorial chemistry , bacillus subtilis , genetics
We describe the design and synthesis of a new series of non‐natural short cationic lipopeptides ( M W = 700) as antimicrobial agents. All of the synthesized lipopeptides were tested against a range of microbes such as G ram‐positive, G ram‐negative bacteria, fungi including methicillin‐resistant S taphylococcus aureus ( MRSA ) and methicillin‐resistant S taphylococcus epidermidis ( MRSE ). By systematic study of design template, we found that three ornithine residues conjugated with myristic acid are minimum requirement for a compound to be an antimicrobial agent. The most potent lipopeptide LP 16 possesses broad‐spectrum antimicrobial activity and has MIC s in the range of 1.5–6.25 μg/mL against E scherichia coli , S . aureus , P seudomonas aeruginosa , B acillus subtilis , and MRSE . All lipopeptides showed high selectivity toward microbial strains as compared to human red blood cells ( HC 50 > 250 μg/mL). Moreover, most potent lipopeptides ( LP 16 and LP 23) did not induce drug resistance in S . aureus even after 15 rounds of passaging. In addition, a representative lipopeptide ( LP 16) showed tryptic stability for 24 h. These results suggest the potential of short cationic lipopeptides to boost the discovery of future antimicrobial therapeutics.