Tackling superbugs in their slime castles: innovative approaches against antimicrobial-resistant biofilm infections
Katharina Richter
+ Author Affiliations
- Author Affiliations
Richter Lab
Department of Surgery
Basil Hetzel Institute for Translational Health Research
The Queen Elizabeth Hospital and
University of Adelaide
37a Woodville Road
Woodville South, SA 5011, Australia
Tel: +61 8 8222 7541
Email: Katharina.Richter@adelaide.edu.au
Microbiology Australia 40(4) 165-168 https://doi.org/10.1071/MA19049
Published: 11 November 2019
Abstract
The rise of ‘superbugs' like methicillin-resistant Staphylococcus aureus threatens human health on a global scale. Bacteria have established many ways to withstand antimicrobial treatments, evade the immune system and protect them from external stressors. Current medical care frequently fails to eradicate multi-drug resistant bacteria, microbial biofilms and small colony variants that can hide from antibiotic treatments inside human cells, therefore, drug discovery and drug development to improve healthcare is pivotal. In this article, novel antimicrobial strategies with extensive activity against multi-drug resistant staphylococci are described, including: * Trojan Horse approaches * multi-pronged strategies * metals * repurposing of drugs * phage therapy. Preclinical validation confirmed safety and efficacy against biofilms and small colony variants in vitro and in vivo. This was the foundation for the translation of two strategies into phase I clinical trials using: (1) deferiprone and galliumprotoporphyrin to disrupt bacterial iron metabolism; and (2) colloidal silver nanoparticles as topical treatments for staphylococcal biofilm-related infections.
References
[1] O’Neill, J. (2014) Antimicrobial resistance: tackling a crisis for the health and wealth of nations. Review on Antimicrobial Resistance.[2] Costerton, J.W. (1999) Bacterial biofilms: a common cause of persistent infections. Science 284, 1318–1322.
| Bacterial biofilms: a common cause of persistent infections.Crossref | GoogleScholarGoogle Scholar | 10334980PubMed |
[3] Richter, K. et al. (2017) Innovative approaches to treat Staphylococcus aureus biofilm-related infections. Essays Biochem. 61, 61–70.
| Innovative approaches to treat Staphylococcus aureus biofilm-related infections.Crossref | GoogleScholarGoogle Scholar | 28258230PubMed |
[4] Reniere, M.L. et al. (2007) Intracellular metalloporphyrin metabolism in Staphylococcus aureus. Biometals 20, 333–345.
| Intracellular metalloporphyrin metabolism in Staphylococcus aureus.Crossref | GoogleScholarGoogle Scholar | 17387580PubMed |
[5] Skaar, E.P. et al. (2004) Iron-source preference of Staphylococcus aureus infections. Science 305, 1626–1628.
| Iron-source preference of Staphylococcus aureus infections.Crossref | GoogleScholarGoogle Scholar | 15361626PubMed |
[6] Cassat, J.E. and Skaar, E.P. (2013) Iron in infection and immunity. Cell Host Microbe 13, 509–519.
| Iron in infection and immunity.Crossref | GoogleScholarGoogle Scholar | 23684303PubMed |
[7] Richter, K. et al. (2016) Mind ‘De GaPP’: in vitro efficacy of deferiprone and gallium-protoporphyrin against Staphylococcus aureus biofilms. Int. Forum Allergy Rhinol. 6, 737–743.
| Mind ‘De GaPP’: in vitro efficacy of deferiprone and gallium-protoporphyrin against Staphylococcus aureus biofilms.Crossref | GoogleScholarGoogle Scholar | 26919404PubMed |
[8] Richter, K. et al. (2017) A topical hydrogel with deferiprone and gallium-protoporphyrin targets bacterial iron metabolism and has antibiofilm activity. Antimicrob. Agents Chemother. 61, e00481-17.
| A topical hydrogel with deferiprone and gallium-protoporphyrin targets bacterial iron metabolism and has antibiofilm activity.Crossref | GoogleScholarGoogle Scholar | 28396543PubMed |
[9] Richter, K. et al. (2017) Deferiprone and gallium-protoporphyrin have the capacity to potentiate the activity of antibiotics in Staphylococcus aureus small colony variants. Front. Cell. Infect. Microbiol. 7, 280.
| Deferiprone and gallium-protoporphyrin have the capacity to potentiate the activity of antibiotics in Staphylococcus aureus small colony variants.Crossref | GoogleScholarGoogle Scholar | 28690982PubMed |
[10] Kelson, A.B. et al. (2013) Gallium-based anti-infectives: targeting microbial iron-uptake mechanisms. Curr. Opin. Pharmacol. 13, 707–716.
| Gallium-based anti-infectives: targeting microbial iron-uptake mechanisms.Crossref | GoogleScholarGoogle Scholar | 23876838PubMed |
[11] Gielen, M. and Tiekink, E.R. (2005) Metallotherapeutic drugs and metal-based diagnostic agents: the use of metals in medicine. John Wiley & Sons, Chichester, UK.
[12] Coraça-Huber, D.C. et al. (2018) Iron chelation destabilizes bacterial biofilms and potentiates the antimicrobial activity of antibiotics against coagulase-negative Staphylococci. Pathog. Dis. 76, fty052.
| Iron chelation destabilizes bacterial biofilms and potentiates the antimicrobial activity of antibiotics against coagulase-negative Staphylococci.Crossref | GoogleScholarGoogle Scholar | 29860413PubMed |
[13] Ooi, M.L. et al. (2018) Safety and efficacy of topical chitogel-deferiprone-gallium protoporphyrin in sheep model. Front. Microbiol. 9, 917.
| Safety and efficacy of topical chitogel-deferiprone-gallium protoporphyrin in sheep model.Crossref | GoogleScholarGoogle Scholar | 29867828PubMed |
[14] Valentine, R. et al. (2010) The efficacy of a novel chitosan gel on hemostasis and wound healing after endoscopic sinus surgery. Am. J. Rhinol. Allergy 24, 70–75.
| The efficacy of a novel chitosan gel on hemostasis and wound healing after endoscopic sinus surgery.Crossref | GoogleScholarGoogle Scholar | 20109331PubMed |
[15] Mohammadpour, M. et al. (2013) Wound healing by topical application of antioxidant iron chelators: kojic acid and deferiprone. Int. Wound J. 10, 260–264.
| Wound healing by topical application of antioxidant iron chelators: kojic acid and deferiprone.Crossref | GoogleScholarGoogle Scholar | 22621771PubMed |
[16] Costa, S.S. et al. (2013) Multidrug efflux pumps in Staphylococcus aureus: an update. Open Microbiol. J. 7, 59–71.
| Multidrug efflux pumps in Staphylococcus aureus: an update.Crossref | GoogleScholarGoogle Scholar | 23569469PubMed |
[17] Parsek, M.R. and Greenberg, E. (2005) Sociomicrobiology: the connections between quorum sensing and biofilms. Trends Microbiol. 13, 27–33.
| Sociomicrobiology: the connections between quorum sensing and biofilms.Crossref | GoogleScholarGoogle Scholar | 15639629PubMed |
[18] Brackman, G. et al. (2016) The quorum sensing inhibitor hamamelitannin increases antibiotic susceptibility of Staphylococcus aureus biofilms by affecting peptidoglycan biosynthesis and eDNA release. Sci. Rep. 6, 20321.
| The quorum sensing inhibitor hamamelitannin increases antibiotic susceptibility of Staphylococcus aureus biofilms by affecting peptidoglycan biosynthesis and eDNA release.Crossref | GoogleScholarGoogle Scholar | 26828772PubMed |
[19] Richter, K. (2017) Towards novel antibiofilm strategies. PhD thesis. The University of Adelaide, Adelaide, Australia. 1–211.
[20] Franci, G. et al. (2015) Silver nanoparticles as potential antibacterial agents. Molecules 20, 8856–8874.
| Silver nanoparticles as potential antibacterial agents.Crossref | GoogleScholarGoogle Scholar | 25993417PubMed |
[21] Richter, K. et al. (2017) Taking the silver bullet colloidal silver particles for the topical treatment of biofilm-related infections. ACS Appl. Mater. Interfaces 9, 21631–21638.
| Taking the silver bullet colloidal silver particles for the topical treatment of biofilm-related infections.Crossref | GoogleScholarGoogle Scholar | 28598149PubMed |
[22] Ooi, M.L. et al. (2018) Topical colloidal silver for the treatment of recalcitrant chronic rhinosinusitis. Front. Microbiol. 9, 720.
| Topical colloidal silver for the treatment of recalcitrant chronic rhinosinusitis.Crossref | GoogleScholarGoogle Scholar | 29696011PubMed |
[23] Cherian, L.M. et al. (2019) Effect of commercial nasal steroid preparation on bacterial growth. Int. Forum Allergy Rhinol. 9, 766–775.
| Effect of commercial nasal steroid preparation on bacterial growth.Crossref | GoogleScholarGoogle Scholar | 30748102PubMed |
[24] Sulakvelidze, A. et al. (2001) Bacteriophage therapy. Antimicrob. Agents Chemother. 45, 649–659.
| Bacteriophage therapy.Crossref | GoogleScholarGoogle Scholar | 11181338PubMed |
[25] Zhang, G. et al. (2018) Bacteriophage effectively kills multidrug resistant Staphylococcus aureus clinical isolates from chronic rhinosinusitis patients. Int. Forum Allergy Rhinol. 8, 406–414.
| Bacteriophage effectively kills multidrug resistant Staphylococcus aureus clinical isolates from chronic rhinosinusitis patients.Crossref | GoogleScholarGoogle Scholar | 29240296PubMed |
[26] Furfaro, L.L. et al. (2018) Bacteriophage therapy: clinical trials and regulatory hurdles. Front. Cell. Infect. Microbiol. 8, 376.
| Bacteriophage therapy: clinical trials and regulatory hurdles.Crossref | GoogleScholarGoogle Scholar | 30406049PubMed |
[27] Rhoads, D.D. et al. (2009) Bacteriophage therapy of venous leg ulcers in humans: results of a phase I safety trial. J. Wound Care 18, 237–243.
| Bacteriophage therapy of venous leg ulcers in humans: results of a phase I safety trial.Crossref | GoogleScholarGoogle Scholar | 19661847PubMed |
[28] Kutter, E. et al. (2010) Phage therapy in clinical practice: treatment of human infections. Curr. Pharm. Biotechnol. 11, 69–86.
| Phage therapy in clinical practice: treatment of human infections.Crossref | GoogleScholarGoogle Scholar | 20214609PubMed |
[29] Leitner, L. et al. (2017) Bacteriophages for treating urinary tract infections in patients undergoing transurethral resection of the prostate: a randomized, placebo-controlled, double-blind clinical trial. BMC Urol. 17, 90.
| Bacteriophages for treating urinary tract infections in patients undergoing transurethral resection of the prostate: a randomized, placebo-controlled, double-blind clinical trial.Crossref | GoogleScholarGoogle Scholar | 28950849PubMed |
