Probing the Mechanism of LAL-32, a Gold Nanoparticle-Based Antibiotic Discovered through Small Molecule Variable Ligand Display

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...

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Bibliographic Details
Published in:Bioconjugate chemistry 2017-07, Vol.28 (7), p.1807-1810
Main Authors: Byrne-Nash, Rose, Lucero, Danielle M, Osbaugh, Niki A, Melander, Roberta J, Melander, Christian, Feldheim, Daniel L
Format: Article
Language:English
Subjects:
Ampicillin
Anti-Bacterial Agents - chemistry
Anti-Bacterial Agents - pharmacology
Antibiotics
Arginine
Bacteria
Bactericidal activity
Cell division
Cell Division - drug effects
Drug Discovery - methods
Drug Resistance, Bacterial
E coli
Escherichia coli - cytology
Escherichia coli - drug effects
Escherichia coli Proteins - antagonists & inhibitors
Gentamicin
Gold
Ligands
Membrane Transport Proteins
Metal Nanoparticles - chemistry
Metal Nanoparticles - therapeutic use
Molecules
Mutants
Nanoparticles
Periplasm
Proteins
Resistant mutant
Small Molecule Libraries
Translocation
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Summary: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.
ISSN:1043-1802
1520-4812
DOI:10.1021/acs.bioconjchem.7b00199