Combating multidrug-resistant Gram-negative bacteria with structurally nanoengineered antimicrobial peptide polymers

Abstract

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.

Predatory Bacteria Attenuate Klebsiella pneumoniae Burden in Rat Lungs

“…Rather, this study was an experimental exercise designed to determine whether predatory bacteria have the ability to reduce bacterial burden in an in vivo mammalian system. Our treatment scheme is similar to that of a recent study examining the efficacy of structurally nanoengineered antimicrobial peptide polymers (SNAPPs) in reducing MDR infections in mice (33). Mice were “infected” with a pathogen ( Acinetobacter baumannii ) and, similarly to our study method, were treated with SNAPPs at 30 min and 4 and 8 h postinoculation before being euthanized at 24 h.…”

Single step fabrication of antimicrobial fibre mats from a bioengineered protein-based polymer

“…The difference found for the antimicrobial activity in S. aureus is most likely due to the ability of the bacterial cells to form aggregates, reducing the direct contact with the fibres [4]. In opposition to antibiotics, which act in specific intracellular targets, AMPs mostly interact with the negatively charged bacterial cell membranes through electrostatic forces, inducing physical changes and damaging the biological membranes [26][27][28]51]. Although not being clearly understood, the antimicrobial action of ABP-CM4 is generally accepted to be a consequence of an interaction with the cell membrane, leading to the formation of transmembrane pores that result in cell death [52].…”

“…Antimicrobial peptides (AMPs) are considered a promising alternative to tackle multidrug resistant bacteria [26][27][28]. This class of small immunomodulatory peptides is found in almost all living organisms, representing the first line of defence of multicellular organisms as part of their innate immune system [26,29].…”

Current Approaches for Exploration of Nanoparticles as Antibacterial Agents

“…Namely, a nanotechnology-based antibacterial agent can be constructed out of several components that possess antimicrobial activities in themselves, such as, for instant, be composed of an antibacterial core material (e.g. metal or metal oxide) surrounded with an antibacterial polymeric shell or coating, in which antibiotic drugs could be incorporated [71]. The core material could further be "prickly," which physically can destroy the bacterial cell wall by a "nano-piercing" process once the polymeric shell has been dissolved, leading to the disruption of bacterial integrity and lysis, as presented in a recent study by Wu et al where zinc-doped copper oxide prickly nanoparticles exhibited high bacterial killing efficiency owing to the provided core particle nanostructure [72].…”