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.
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G.G.Q. acknowledges financial support from the Australian Research Council under the Future Fellowship (FT110100411) scheme. E.C.R. acknowledges financial support from the Australian Government, Department of Industry, Innovation and Science. S.J.L. acknowledges the Australian Government for providing an International Postgraduate Research Scholarship (IPRS) and an Australian Postgraduate Award (APAInt). The authors thank the Advanced Fluorescence Imaging Platform at the Materials Characterisation and Fabrication Platform (The University of Melbourne) for instrument access. The authors thank B. Hibbs for assistance with the Delta Vision OMX V4 BLAZE, S. Lowe for technical laboratory assistance and J. Li for the CMDR bacterial strains.
The authors declare no competing financial interests.
Supplementary Materials and Instrumentation, Supplementary Figures 1–36, legends for Supplementary Videos 1 and 2, Supplementary Tables 1–11, Supplementary References. (PDF 5572 kb)
A sample 3D view of an E. coli cell that demonstrates the membrane association of SNAPPs after treatment. (MOV 1499 kb)
A sample 3D view of an E. coli cell that demonstrates the cell internalization of SNAPPs after treatment. (MOV 1648 kb)
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Lam, S., O'Brien-Simpson, N., Pantarat, N. et al. Combating multidrug-resistant Gram-negative bacteria with structurally nanoengineered antimicrobial peptide polymers. Nat Microbiol 1, 16162 (2016). https://doi.org/10.1038/nmicrobiol.2016.162
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