Combinatorial effects of juglone and fusidic acid in controlling Staphylococcus aureus biofilms

<p>Chronic skin wounds are disruptions of the skin that remain in the inflammatory state for more than one month. They affect approximately 3% of the people with more than 60 years and are mostly associated with diabetic foot, pressure ulcers, blood vessels or trauma<sup>1</sup>. Besides that, it is expected that 578 million people worldwide will suffer from the disease by 2030, that will subsequently increase the risk of developing infection and potentially result in amputation or osteomyelitis<sup>2</sup>. One of the main difficulties in the wound healing process is the fact that bacteria persist due to biofilm formation. Biofilms delay not only healing, but they also make bacteria more resistant to the antimicrobial therapy. Among the bacteria present at the wound site, <em>Staphylococcus aureus</em> was found to be one of the most prevalent biofilm producers<sup>3</sup>. In this sense, other alternatives to fight biofilm infections should be considered due to the resistance to the current antibiotics. One possible strategy consists of using antibiotic adjuvants to enhance the activity of current drugs and to minimize or even block resistance. For that, plants are used as a resource of such adjuvant compounds. The use of natural compounds from plants have been applied in skin wound care for millennials, generating a lot of interest from the scientific community. Indeed, not only are phytochemicals great antibiotic potentiators but they also possess numerous therapeutic properties<sup>4</sup>. Therefore, in this study, the phenolic compound juglone (5-hydroxy-1,4-naphtoquinone) was investigated, alone and combined with fusidic acid antibiotic, for its potential to eradicate pre-formed <em>S. aureus</em> biofilms. Although no biomass removal was observed, there was a total loss of cell culturability (about 6-log CFU/cm<sup>2</sup> reduction) and a considerable metabolic activity reduction. Juglone reduced metabolic activity by 83% both alone and in combination with fusidic acid, which is an improvement over the 70% reduction obtained by the antibiotic. Therefore, an additive interaction of juglone when combined with fusidic acid was attained in the control of <em>S. aureus</em> biofilms. In addition, according with Lipinsksi’s rule of five, it was assessed that juglone possesses important molecular properties with respect to pharmacokinetics in the human body. Overall, this study reveals the great potential for the topical application of juglone as an adjuvant to the widely used fusidic acid to combat multi-drug resistant wound infections.  </p> <p> </p> <p>References:</p> <p>(1)         Manu, C., et al. J. Wound Care 27.3 (2018): 186–192.</p> <p>(2)         International Diabetes Federation. https://www.diabetesatlas.org (accessed May 27, 2020).</p> <p>(3)         Kadam, S., et al. Biomedicines 7.2 (2019): 35.</p> <p>(4)         Borges, A.; et al. Molecules 21.7 (2016): 877.</p> <p> </p> <p><strong>Acknowledgements: </strong>This work was financially supported by: Base Funding - UIDB/00511/2020 of the Laboratory for Process Engineering, Environment, Biotechnology and Energy – LEPABE - funded by national funds through the FCT/MCTES (PIDDAC); - PTDC/BII-BTI/30219/2017 - POCI-01-0145-FEDER-030219; POCI-01-0247-FEDER-035234; POCI-01-145-FEDER-006939, funded by FEDER funds through COMPETE2020 – Programa Operacional Competitividade e Internacionalização (POCI) and by national funds (PIDDAC) through CEECIND/01261/2017 (Anabela Borges), SFRH/BD/138217/2018 (Diana Oliveira) and SFRH/BSAB/150379/2019 (Manuel Simões).</p>