Princeton
Docket # 11-2663
Researchers
at Princeton University created novel peptide derivatives of the antimicrobial
peptide Microcin J25 (MccJ25) with multiple amino acid substitutions and potent
activity against Gram-negative bacteria. The most potent MccJ25 variants
displayed up to a nearly 5-fold improvement in bacterial growth inhibition
action against E. coli and the pathogenic Salmonella strain S.
Newport.
Few
new classes of antibiotics have been discovered in the past decades and the
emergence of multi-drug resistant organisms demands new antibiotics to treat
infections. MccJ25 is a promising
new candidate for antimicrobial use because of its potent mechanism of action by
inhibiting bacterial RNA polymerase. The MccJ25 derivatives described here have
been isolated by genetic modification and have higher potency than the wild-type
antibiotic. Unlike the cationic antimicrobial peptides, MccJ25 derivatives can
be produced in high yield in bacterial hosts and are extremely stable in
conditions of extreme temperature or chemical denaturation due to the threaded
lasso structure.
Besides
the application as an antimicrobial therapeutic, the
MccJ25 derivatives also hold the promise to be the next-generation food
preservative. Nisin,
a polycyclic antibacterial peptide, is widely used as a food preservative for
its suppression of gram-positive spoilage and pathogenic bacteria. However, it is not effective against
Gram-negative bacteria, yeast or moulds.
The stability of nisin during storage is dependent upon incubation
temperature, length of storage and pH.
A typical cheese pasteurization process (85¿105°C
for 5¿10 min at pH 5.6¿5.8)
results in 20-30% loss of activity, and storage at 25
°C
for 30 weeks leads to 40% loss. In
addition, nisin
is usually naturally produced from Streptococcus
lactis
cultured on milk, and thus may not be safe to be used by people with an allergy
to milk protein or with lactose intolerance. The MccJ25 derivatives, with high thermal
stability and specificity against gram-negative bacteria, are anticipated to be
a better antimicrobial food preservative.
Applications
·
Antimicrobial therapeutic
·
Food preservative
Advantages
·
5-fold improvement in bacterial growth inhibition
·
Exceptional stability towards thermal, and chemical denaturation
·
Proteases Resistance
·
Ability to expand SAR on MccJ25
Publication
Pan
SJ, Link AJ, (2011) Sequence Diversity in the Lasso Peptide Framework: Discovery
of Functional Microcin J25 Variants with Multiple Amino Acid Substitutions.
J
Am Chem Soc