TY - JOUR
T1 - Combined Efficacy of an Antimicrobial Cationic Peptide Polymer with Conventional Antibiotics to Combat Multidrug-Resistant Pathogens
AU - Thappeta, Kishore R.V.
AU - Vikhe, Yogesh S.
AU - Yong, Adeline M.H.
AU - Chan-Park, Mary B.
AU - Kline, Kimberly A.
PY - 2020/5/8
Y1 - 2020/5/8
N2 - 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.
AB - 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.
KW - antimicrobial peptide
KW - biofilm therapeutics
KW - biofilm-associated infection
KW - E. coli
KW - MRSA
KW - VRE
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UR - http://www.scopus.com/inward/citedby.url?scp=85084380082&partnerID=8YFLogxK
U2 - 10.1021/acsinfecdis.0c00016
DO - 10.1021/acsinfecdis.0c00016
M3 - Article
C2 - 32138506
AN - SCOPUS:85084380082
SN - 2373-8227
VL - 6
SP - 1228
EP - 1237
JO - ACS Infectious Diseases
JF - ACS Infectious Diseases
IS - 5
ER -