The Antibacterial and Wound Healing Properties of Natural Products: A Review on Plant Species with Therapeutic Potential against Staphylococcus aureus Wound Infections.

Wounds of an acute or chronic etiology affect millions of people worldwide, with increasing prevalence every year. Microbial infections are one of the main causes that impair the wound healing process, and Staphylococcus aureus, a commensal member of the skin microbiota, is one of the main causative agents of wound infections. Crucially, a high proportion of these infections are caused by methicillin-resistant Staphylococcus aureus, which, in addition to ß-lactams, has acquired resistance to almost all the antibacterial agents used to treat it, limiting therapeutic options. Studies on the antimicrobial and healing activities of extracts, essential oils, or metabolites obtained from native plants have been reported in many countries that have a diverse flora and traditions with the use of medicinal plants for the treatment of wound infections. Due to their great chemical diversity, plants have proven to be promising sources of bioactive molecules for the discovery and development of new drugs or strategies for the treatment of wounds. This review highlights the main herbal preparations that have antimicrobial and healing activities with potential for the treatment of wound infections caused by Staphylococcus aureus.

Synergistic Antifungal Interaction between Pseudomonas aeruginosa LV Strain Metabolites and Biogenic Silver Nanoparticles against Candida auris.

Candida auris has been found to be a persistent colonizer of human skin and a successful pathogen capable of causing potentially fatal infection, especially in immunocompromised individuals. This fungal species is usually resistant to most antifungal agents and has the ability to form biofilms on different surfaces, representing a significant therapeutic challenge. Herein, the effect of metabolites of Pseudomonas aeruginosa LV strain, alone and combined with biologically synthesized silver nanoparticles (bioAgNP), was evaluated in planktonic and sessile (biofilm) cells of C. auris. First, the minimal inhibitory and fungicidal concentration values of 3.12 and 6.25 µg/mL, respectively, were determined for F4a, a semi-purified bacterial fraction. Fluopsin C and indolin-3-one seem to be the active components of F4a. Like the semi-purified fraction, they showed a time- and dose-dependent fungicidal activity. F4a and bioAgNP caused severe changes in the morphology and ultrastructure of fungal cells. F4a and indolin-3-one combined with bioAgNP exhibited synergistic fungicidal activity against planktonic cells. F4a, alone or combined with bioAgNP, also caused a significant decrease in the number of viable cells within the biofilms. No cytotoxicity to mammalian cells was detected for bacterial metabolites combined with bioAgNP at synergistic concentrations that presented antifungal activity. These results indicate the potential of F4a combined with bioAgNP as a new strategy for controlling C. auris infections.

Synergistic antifungal interaction of N-(butylcarbamothioyl) benzamide and amphotericin B against Cryptococcus neoformans.

Introduction: Cryptococcus neoformans is one of the leading causes of invasive fungal infections worldwide. Cryptococcal meningoencephalitis is the main challenge of antifungal therapy due to high morbidity and mortality rates, especially in low- and middle-income countries. This can be partly attributed to the lack of specific diagnosis difficulty accessing treatment, antifungal resistance and antifungal toxicity. Methods: In the present study, the effect of the synthetic thiourea derivative N-(butylcarbamothioyl) benzamide (BTU-01), alone and combined with amphotericin B (AmB), was evaluated in planktonic and sessile (biofilm) cells of C. neoformans. Results: BTU-01 alone exhibited a fungistatic activity with minimal inhibitory concentrations (MICs) ranging from 31.25 to 62.5 µg/mL for planktonic cells; and sessile MICs ranging from 125.0 to 1000.0 µg/mL. BTU-01 caused a concentration-dependent inhibitory activity on cryptococcal urease and did not interfere with plasma membrane fluidity. Molecular docking was performed on Canavalia ensiformis urease, and BTU-01 showed relevant interactions with the enzyme. The combination of BTU-01 and AmB exhibited synergistic fungicidal activity against planktonic and sessile cells of C. neoformans. Microscopic analysis of C. neoformans treated with BTU-01, alone or combined with AmB, revealed a reduction in cell and capsule sizes, changes in the morphology of planktonic cells; a significant decrease in the number of cells within the biofilm; and absence of exopolymeric matrix surrounding the sessile cells. Neither hemolytic activity nor cytotoxicity to mammalian cells was detected for BTU-01, alone or combined with AmB, at concentrations that exhibited antifungal activity. BTU-01 also displayed drug-likeness properties. Conclusion: These results indicate the potential of BTU-01, for the development of new strategies for controlling C. neoformans infections.

Antifungal Combination of Ethyl Acetate Extract of Poincianella pluviosa (DC.) L. P. Queiros Stem Bark With Amphotericin B in Cryptococcus neoformans.

Cryptococcus neoformans is the leading cause of cryptococcosis, an invasive and potentially fatal infectious disease. Therapeutic failures are due to the increase in antifungal resistance, the adverse effects of drugs, and the unavailability of therapeutic regimens in low-income countries, which limit the treatment of cryptococcosis, increasing the morbidity and mortality associated with these infections. Thus, new antifungal drugs and innovative strategies for the cryptococcosis treatment are urgently needed. The aim of the present study was to evaluate the effect of ethyl acetate fraction (EAF) of Poincianella pluviosa stem bark on planktonic and biofilm mode of growth of C. neoformans. Furthermore, the interaction between the EAF and amphotericin B (AmB) was evaluated in vitro and in Galleria mellonella infection model. Minimal inhibitory concentrations (MICs) of EAF ranged from 125.0 to >1,000.0 µg/ml and >1,000.0 µg/ml for planktonic and sessile cells, respectively. The combination between EAF and AmB exhibited a synergistic fungicidal activity toward C. neoformans, with a fractional inhibitory concentration index (FICI) ranging from 0.03 to 0.06 and 0.08 to 0.28 for planktonic and sessile cells, respectively. Microscopy analyses of planktonic C. neoformans cells treated with EAF, alone or combined with AmB, revealed morphological and ultrastructural alterations, including loss of integrity of the cell wall and cell membrane detachment, suggesting leakage of intracellular content, reduction of capsule size, and presence of vacuoles. Moreover, EAF alone or combined with AmB prolonged the survival rate of C. neoformans-infected G. mellonella larvae. These findings indicate that P. pluviosa may be an important source of new compounds that can be used as a fungus-specific adjuvant for the treatment of cryptococcosis.

Hydrogel Containing Oleoresin From Copaifera officinalis Presents Antibacterial Activity Against Streptococcus agalactiae.

Streptococcus agalactiae or Group B Streptococcus (GBS) remains a leading cause of neonatal infections worldwide; and the maternal vaginal-rectal colonization increases the risk of vertical transmission of GBS to neonates and development of infections. This study reports the in vitro antibacterial effect of the oleoresin from Copaifera officinalis Jacq. L. in natura (copaiba oil) and loaded into carbomer-hydrogel against planktonic and sessile cells of GBS. First, the naturally extracted copaiba oil was tested for the ability to inhibit the growth and metabolic activity of planktonic and sessile GBS cells. The time-kill kinetics showed that copaiba oil exhibited a dose-dependent bactericidal activity against planktonic GBS strains, including those resistant to erythromycin and/or clindamycin [minimal bactericidal concentration (MBC) ranged from 0.06 mg/mL to 0.12 mg/mL]. Copaiba oil did not inhibit the growth of different Lactobacillus species, the indigenous members of the human microbiota. The mass spectral analyses of copaiba oil showed the presence of diterpenes, and the kaurenoic acid appears to be one of the active components of oleoresin from C. officinalis related to antibacterial activity against GBS. Microscopy analyses of planktonic GBS cells treated with copaiba oil revealed morphological and ultrastructural alterations, displaying disruption of the cell wall, damaged cell membrane, decreased electron density of the cytoplasm, presence of intracellular condensed material, and asymmetric septa. Copaiba oil also exhibited antibacterial activity against established biofilms of GBS strains, inhibiting the viability of sessile cells. Low-cost and eco-friendly carbomer-based hydrogels containing copaiba oil (0.5% - CARB-CO 0.5; 1.0% - CARB-CO 1.0) were then developed. However, only CARB-CO 1.0 preserved the antibacterial activity of copaiba oil against GBS strains. This formulation was homogeneous, soft, exhibited a viscoelastic behavior, and showed good biocompatibility with murine vaginal mucosa. Moreover, CARB-CO 1.0 showed a slow and sustained release of the copaiba oil, killing the planktonic and sessile (established biofilm) cells and inhibiting the biofilm formation of GBS on pre-coated abiotic surface. These results indicate that carbomer-based hydrogels may be useful as topical systems for delivery of copaiba oil directly into de vaginal mucosa and controlling S. agalactiae colonization and infection.

Phenotypic characteristics and transcriptome profile of Cryptococcus gattii biofilm.

In this study, we characterized Cryptococcus gattii biofilm formation in vitro. There was an increase in the density of metabolically active sessile cells up to 72 h of biofilm formation on polystyrene and glass surfaces. Scanning electron microscopy and confocal laser scanning microscopy analysis revealed that in the early stage of biofilm formation, yeast cells adhered to the abiotic surface as a monolayer. After 12 h, extracellular fibrils were observed projecting from C. gattii cells, connecting the yeast cells to each other and to the abiotic surface; mature biofilm consisted of a dense network of cells deeply encased in an extracellular polymeric matrix. These features were also observed in biofilms formed on polyvinyl chloride and silicone catheter surfaces. We used RNA-Seq-based transcriptome analysis to identify changes in gene expression associated with C. gattii biofilm at 48 h compared to the free-floating planktonic cells. Differential expression analysis showed that 97 and 224 transcripts were up-regulated and down-regulated in biofilm, respectively. Among the biological processes, the highest enriched term showed that the transcripts were associated with cellular metabolic processes, macromolecule biosynthetic processes and translation.