Combating multidrug-resistant Gram-negative bacteria with structurally nanoengineered antimicrobial peptide polymers.
With the recent emergence of reports on resistant Gram-negative 'superbugs', infections caused by multidrug-resistant (MDR) Gram-negative bacteria have been named as one of the most urgent global health threats due to the lack of effective and biocompatible drugs. Here, we show that a class of antimicrobial agents, termed 'structurally nanoengineered antimicrobial peptide polymers' (SNAPPs) exhibit sub-μM activity against all Gram-negative bacteria tested, including ESKAPE and colistin-resistant and MDR (CMDR) pathogens, while demonstrating low toxicity. SNAPPs are highly effective in combating CMDR Acinetobacter baumannii infections in vivo, the first example of a synthetic antimicrobial polymer with CMDR Gram-negative pathogen efficacy. Furthermore, we did not observe any resistance acquisition by A. baumannii (including the CMDR strain) to SNAPPs. Comprehensive analyses using a range of microscopy and (bio)assay techniques revealed that the antimicrobial activity of SNAPPs proceeds via a multimodal mechanism of bacterial cell death by outer membrane destabilization, unregulated ion movement across the cytoplasmic membrane and induction of the apoptotic-like death pathway, possibly accounting for why we did not observe resistance to SNAPPs in CMDR bacteria. Overall, SNAPPs show great promise as low-cost and effective antimicrobial agents and may represent a weapon in combating the growing threat of MDR Gram-negative bacteria.
Polymer Science Group, Department of Chemical &Biomolecular Engineering, The University of Melbourne, Parkville, Victoria 3010, Australia.
Shu J
SJ
Lam
Melbourne Dental School and The Bio21 Institute of Molecular Science and Biotechnology, Oral Health CRC, The University of Melbourne, Parkville, Victoria 3010, Australia.
Neil M
http://orcid.org/0000-0001-8462-5603
NM
O'Brien-Simpson
Melbourne Dental School and The Bio21 Institute of Molecular Science and Biotechnology, Oral Health CRC, The University of Melbourne, Parkville, Victoria 3010, Australia.
Namfon
N
Pantarat
Polymer Science Group, Department of Chemical &Biomolecular Engineering, The University of Melbourne, Parkville, Victoria 3010, Australia.
Adrian
A
Sulistio
Polymer Science Group, Department of Chemical &Biomolecular Engineering, The University of Melbourne, Parkville, Victoria 3010, Australia.
Edgar H H
EH
Wong
Melbourne Dental School and The Bio21 Institute of Molecular Science and Biotechnology, Oral Health CRC, The University of Melbourne, Parkville, Victoria 3010, Australia.
Yu-Yen
YY
Chen
Melbourne Dental School and The Bio21 Institute of Molecular Science and Biotechnology, Oral Health CRC, The University of Melbourne, Parkville, Victoria 3010, Australia.
Jason C
JC
Lenzo
Melbourne Dental School and The Bio21 Institute of Molecular Science and Biotechnology, Oral Health CRC, The University of Melbourne, Parkville, Victoria 3010, Australia.
James A
JA
Holden
Polymer Science Group, Department of Chemical &Biomolecular Engineering, The University of Melbourne, Parkville, Victoria 3010, Australia.|School of Pharmacy and Medical Sciences, Division of Health Sciences, The University of South Australia, Adelaide, South Australia 5000, Australia.
Anton
A
Blencowe
Melbourne Dental School and The Bio21 Institute of Molecular Science and Biotechnology, Oral Health CRC, The University of Melbourne, Parkville, Victoria 3010, Australia.
Eric C
http://orcid.org/0000-0002-6618-4856
EC
Reynolds
Polymer Science Group, Department of Chemical &Biomolecular Engineering, The University of Melbourne, Parkville, Victoria 3010, Australia.
Greg G
GG
Qiao
D000151:Acinetobacter Infections / Q000188:drug therapy / Q000382:microbiology; D040981:Acinetobacter baumannii / Q000187:drug effects / Q000472:pathogenicity; D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D024901:Drug Resistance, Multiple, Bacterial; D004926:Escherichia coli / Q000187:drug effects / Q000472:pathogenicity; D006090:Gram-Negative Bacteria / Q000187:drug effects*; D016905:Gram-Negative Bacterial Infections / Q000188:drug therapy / Q000382:microbiology; D051379:Mice; D053758:Nanoparticles / Q000737:chemistry; D036103:Nanotechnology / Q000191:economics / Q000379:methods; D010538:Peritonitis / Q000188:drug therapy / Q000382:microbiology
D023181:Antimicrobial Cationic Peptides