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

• 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
• ISSN: 1043-1802; 1520-4812
• DOI: 10.1021/acs.bioconjchem.7b00199

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.