Versatility of targeted antibiotic-loaded gold nanoconstructs for the treatment of biofilm-associated bacterial infections

Abstract

Background: We previously demonstrated that a photoactivatable therapeutic approach employing antibiotic-loaded, antibody-conjugated, polydopamine (PDA)-coated gold nanocages (AuNCs) could be used for the synergistic killing of bacterial cells within a biofilm. The approach was validated with a focus on Staphylococcus aureus using an antibody specific for staphylococcal protein A (Spa) and an antibiotic (daptomycin) active against Gram-positive cocci including methicillin-resistant S. aureus (MRSA). However, an important aspect of this approach is its potential therapeutic versatility.

Methods: In this report, we evaluated this versatility by examining the efficacy of AuNC formulations generated with alternative antibodies and antibiotics targeting S. aureus and alternative combinations targeting the Gram-negative pathogen Pseudomonas aeruginosa.

Results: The results confirmed that daptomycin-loaded AuNCs conjugated to antibodies targeting two different S. aureus lipoproteins (SACOL0486 and SACOL0688) also effectively kill MRSA in the context of a biofilm. However, our results also demonstrate that antibiotic choice is critical. Specifically, ceftaroline and vancomycin-loaded AuNCs conjugated to anti-Spa antibodies were found to exhibit reduced efficacy relative to daptomycin-loaded AuNCs conjugated to the same antibody. In contrast, gentamicin-loaded AuNCs conjugated to an antibody targeting a conserved outer membrane protein were highly effective against P. aeruginosa biofilms.

Conclusions: These results confirm the therapeutic versatility of our approach. However, to the extent that its synergistic efficacy is dependent on the ability to achieve both a lethal photothermal effect and the thermally controlled release of a sufficient amount of antibiotic, they also demonstrate the importance of carefully designing appropriate antibody and antibiotic combinations to achieve the desired therapeutic synergy.

Keywords:

• Photothermal killing
• Staphylococcus aureus
• Pseudomonas aeruginosa
• biofilms
• gold nanocages

Acknowledgements

The authors would like to acknowledge Dmitry A. Nedosekin for technical assistance with PTM experiments.

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

This work was funded by a kind gift from Robert H. Schmidt, MD and the Texas Hip and Knee Centre and in part by a grant [R56-AI093126] from the National Institute of Allergy and Infectious Diseases. Support was also provided by Arkansas Biosciences Institute and the Centre for Advanced Surface Engineering from NSF EPSCoR OIA 1457888. T.W. was supported by the Arkansas Breast Cancer Research Program. Additional support was provided by core facilities supported by the Centre for Microbial Pathogenesis and Host Inflammatory Responses [P20-GM103450] and the Translational Research Institute [UL1TR000039].