Phytochemicals as adjuvants of topical antibiotics to treat biofilm related Staphylococcus aureus wound infections

Diabetic foot ulcers (DFUs) are a complex secondary complication that affect the lower extremities caused by diabetes mellitus. More than half of the DFUs are colonized with Staphylococcus aureus and infection progresses due to the immunosuppression triggered by the disease^1,2. Typically, the treatment includes the use of systemic antibiotics, however, that may result in antibiotic resistance and the risk of drug-related toxic effects³. To minimize these negative impacts the use of topical antibiotics is proposed, especially in combination with natural adjuvants. In this study, 2 different plant-based secondary metabolites (phytochemicals) namely, a phenolic compound (chalcone) and a sesquiterpenoid constituent of essential oils (farnesol) were selected to be tested as antibiotic potentiators. After the determination of the minimum inhibitory and bactericidal concentrations (MIC and MBC) of each molecule against a clinical S. aureus isolate from diabetic foot wound (MJMC109), it was evaluated their potentiation effect on the antibiotics mupirocin and gentamicin through the disc diffusion method. Then, the combined effect of both phytochemicals and antibiotics were evaluated on the potential to eradicate a pre-formed S. aureus biofilm. The results showed a significant biomass removal and culturability reduction with the combination of chalcone with mupirocin and farnesol with gentamicin when compared with its constituents (an increase of at least 20% on biomass removal and 1-log CFU/mL reduction). Farnesol combined with mupirocin was able to significantly reduce the cell culturability (4-log CFU/mL). With respect to the metabolic activity, only chalcone combined with mupirocin was able to increase in 20% the effect when compared to its counterparts. Overall, this study reveals the great potential for the topical application of different phytochemicals as adjuvants to mupirocin to combat multi-drug resistant wound infections.

References:

¹ Lipsky, B. A., et al. Clinical Infectious Diseases 39.7 (2004): 885–910.

² Kadam, S., et al. Biomedicines 7.2 (2019): 35.

³ Afonso, A., et al. International journal of molecular sciences 22.15 (2021): 8278.

Acknowledgements:

This research was funded by: LA/P/0045/2020 (ALiCE), UIDB/00511/2020 and UIDP/00511/2020 (LEPABE) funded by national funds through the FCT/MCTES (PIDDAC; Lisbon, Portugal). Projects PTDC/BIIBTI/30219/2017—POCI-01-0145-FEDER-030219, POCI-01-145-FEDER-006939, POCI-01-0247-FEDER035234, POCI-01-0247-FEDER-072237, funded by FEDER funds through COMPETE2020—Programa Operacional Competitividade e Internacionalização (POCI) and by national funds (PIDDAC) through FCT/MCTES; national funds from Fundação para a Ciência e a Tecnologia (grant numbers: UIDP/ 04378/2020, UIDB/04378/2020, and 2020.01423.CEECIND/CP1596/CT0003); Project “HealthyWaters— Identification, Elimination, Social Awareness and Education of Water Chemical and Biological Micropollutants with Health and Environmental Implications”, with reference NORTE-01-0145-FEDER000069, supported by Norte Portugal Regional Operational Programme (NORTE 2020) under the PORTUGAL 2020 Partnership Agreement through the European Regional Development Fund (ERDF). Grant attributed by Portuguese Foundation for Science and Technology (FCT) to Diana Oliveira (SFRH/BD/138217/2018). Anabela Borges thanks the FCT for the financial support of her work contract through the Scientific Employment Stimulus—Individual Call—[CEECIND/01261/2017].