Probing the Mechanism of LAL-32, a Gold Nanoparticle-Based Antibiotic Discovered through Small Molecule Variable Ligand Display.
Rose Byrne-NashDanielle M LuceroNiki A OsbaughRoberta J MelanderRoberta J MelanderDaniel L FeldheimPublished in: Bioconjugate chemistry (2017)
The unrelenting rise of antimicrobial-resistant bacteria has necessitated the search for novel antibiotic solutions. Herein we describe further mechanistic studies on a 2.0-nm-diameter gold nanoparticle-based antibiotic (designated LAL-32). This antibiotic exhibits bactericidal activity against the Gram-negative bacterium Escherichia coli at 1.0 μM, a concentration significantly lower than several clinically available antibiotics (such as ampicillin and gentamicin), and acute treatment with LAL-32 does not give rise to spontaneous resistant mutants. LAL-32 treatment inhibits cellular division, daughter cell separation, and twin-arginine translocation (Tat) pathway dependent shuttling of proteins to the periplasm. Furthermore, we have found that the cedA gene imparts increased resistance to LAL-32, and shown that an E. coli cedA transposon mutant exhibits increased susceptibility to LAL-32. Taken together, these studies further implicate cell division pathways as the target for this nanoparticle-based antibiotic and demonstrate that there may be inherently higher barriers for resistance evolution against nanoscale antibiotics in comparison to their small molecule counterparts.
Keyphrases
- small molecule
- escherichia coli
- gram negative
- multidrug resistant
- single cell
- cell therapy
- nitric oxide
- stem cells
- staphylococcus aureus
- photodynamic therapy
- copy number
- intensive care unit
- respiratory failure
- hepatitis b virus
- cystic fibrosis
- combination therapy
- biofilm formation
- replacement therapy
- aortic dissection
- transcription factor
- smoking cessation
- high speed