Editors' ChoiceInfectious Disease

Resistance is futile

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Science Translational Medicine  16 Aug 2017:
Vol. 9, Issue 403, eaao4205
DOI: 10.1126/scitranslmed.aao4205

Abstract

Combining tandem peptides that localize toxins to bacterial membranes with scaffolds that target these payloads to the lungs combats drug resistant bacteria without off-target effects.

In the Star Trek universe, the Borg are one of the most feared adversaries. This race—part living, part machine—functions as a single entity, growing ever stronger by mutating to integrate the strengths of each race they conquer. In our universe, drug resistant bacteria have become challenging foes by using some of these same tactics. These pathogens—including methicillin-resistant Staphylococcus aureus (MRSA) and multi-drug resistant Pseudomonas aeruginosa—mutate in response to selection pressure caused by widely prescribed antibiotics. Further, new drugs for resistant strains are difficult to develop because of poor penetration into bacteria and the protective biofilms that bacterial colonies form, along with off-target toxicity to host cells. Thwarting an attack by such a formidable enemy requires a multipronged strategy.

Kwon and colleagues tackled this challenge by loading a novel tandem peptide in porous silicon nanoparticles (pSiNPs). The peptide construct is built from a bacterial toxin linked to one of 25 peptides known to interact with bacterial membranes. This peptide library was screened in culture to identify a construct with high anti-infective activity that minimized off-target effects in mammalian cells. The selected construct was 32-fold more potent than the toxin alone, and 128-fold more potent than the membrane-interacting domain alone. The tandem peptide was also selective, inhibiting both strains of gram-negative bacteria tested but not a gram-positive pathogen. Importantly, lung isolates from human patients were susceptible to the tandem peptide—even isolates that were resistant to all first-line antibiotics tested. During lung instillation in mice, the construct caused labored breathing and inflammation, both of which were absent when the construct was loaded in pSiNPs to localize the peptide to the lungs. In mice challenged with P. aeruginosa, all mice treated with peptide-pSiNPs survived compared with 10% that received vehicle treatment. This efficacy was accompanied by a 104 to 106 reduction in bacteria.

This work combined peptide toxins linked to membrane-targeting domains with a biomaterial scaffold that localizes the construct to the lungs. Although additional studies are needed to test if this strategy synergizes with other drugs and limits the development of resistance, this approach might just help keep you and your next generation safe.

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