Combating multidrug-resistant Gram-negative bacteria with structurally nanoengineered antimicrobial peptide polymers.
Shu J LamNeil M O'Brien-SimpsonNamfon PantaratAdrian SulistioEdgar H H WongYu-Yen ChenJason C LenzoJames A HoldenAnton BlencoweEric C ReynoldsGreg G QiaoPublished in: Nature microbiology (2016)
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.
Keyphrases
- multidrug resistant
- gram negative
- acinetobacter baumannii
- drug resistant
- cell death
- global health
- low cost
- klebsiella pneumoniae
- staphylococcus aureus
- high throughput
- public health
- high resolution
- oxidative stress
- single cell
- cell cycle arrest
- single molecule
- emergency department
- cystic fibrosis
- signaling pathway
- chronic pain
- machine learning
- deep learning
- optical coherence tomography
- drug induced
- big data
- adverse drug
- high speed