posted on 2020-03-13, 16:03authored byKishore R. V. Thappeta, Yogesh S. Vikhe, Adeline M. H. Yong, Mary B. Chan-Park, Kimberly A. Kline
Antibiotic-resistant
infections are predicted to kill 10 million people worldwide per year
by 2050 and to cost the global economy 100 trillion USD. Novel approaches
and alternatives to conventional antibiotics are urgently required
to combat antimicrobial resistance. We have synthesized a chitosan-based
oligolysine antimicrobial peptide, CSM5-K5 (where CSM denotes chitosan
monomer repeat units and K denotes lysine amino acid repeat units),
that targets multidrug-resistant (MDR) bacterial species. Here, we
show that CSM5-K5 exhibits rapid bactericidal activity against methicillin-resistant Staphylococcus aureus (MRSA), MDR Escherichia coli, and vancomycin-resistant Enterococcus faecalis (VRE). Combinatorial therapy of CSM5-K5 with antibiotics to which
each organism is otherwise resistant restores sensitivity to the conventional
antibiotic. CSM5-K5 alone significantly reduced preformed bacterial
biofilm by 2–4 orders of magnitude and, in combination with
conventional antibiotics, reduced preformed biofilm by more than 2–3
orders of magnitude at subinhibitory concentrations. Moreover, using
a mouse excisional wound infection model, CSM5-K5 treatment reduced
bacterial burdens by 1–3 orders of magnitude and acted synergistically
with oxacillin, vancomycin, and streptomycin to clear MRSA, VRE, and
MDR E. coli, respectively. Importantly, little
to no resistance against CSM5-K5 arose for any of the three MDR bacteria
during 15 days of serial passage. Furthermore, low level resistance
to CSM5-K5 that did arise for MRSA conferred increased susceptibility
(collateral sensitivity) to the β-lactam antibiotic oxacillin.
This work demonstrates the feasibility and benefits of using this
synthetic cationic peptide as an alternative to, or in combination
with, traditional antibiotics to treat infections caused by MDR bacteria.