# Honey Therapy in Diabetic Foot Ulcers: A Promising Strategy for Effective Wound Healing
## 4 Honey's Antimicrobial Properties
### Non-Peroxide Antimicrobial Activity
#### 4.2.3 Phenolic Content  
Chemically, phenolics are compounds that possess aromatic rings with one or more hydroxyl groups [117]. The presence of polyphenols was already recognized in food as an important factor in promoting microbiological safety [118]. In honey, polyphenols have been reported as non-peroxide antimicrobial elements [69], promoting antioxidant and anti-inflammatory properties, as well as conferring particular characteristics such as the color and flavor, which depend on the botanical origin [15; 71]. The most available types identified in honey are phenolic acids (benzoic and cinnamic acids) and flavonoids (flavonols, flavones, and flavanones) [71]. To date, a review involving 536 monofloral honey types reported 161 different phenolic compounds, with caffe acid, gallic acid, ferulic acid, and quercetin being the most prevalent in monofloral honey [119].  
Notably, polyphenols can contribute to honey's antimicrobial activity by elevating the H\({}_{2}\)O\({}_{2}\) levels [68]. Additionally, the presence of polyphenols in honey in low concentrations caused pro-oxidant activity, leading to the bacterial DNA being degraded, whereas in high concentrations the polyphenols were positively associated with bacteriostatic activity [120]. A honey sample with a higher total phenolic content (TPC) also presented higher ferric-reducing antioxidant power (FRAP) and 2,2-diphenyl-1-picrylhydrazyl (DPPH) antioxidant activity levels [121]. Furthermore, greater effectiveness against MRSA and _E. faecalis_ was observed in honey with a higher TPC [122]. The addition of propolis to honey samples increased the amounts of phenolic compounds, which could partially explain the increased efficacy of this synergism against _S. aureus_ and _E. coli_[62]. In fact, it seems that the TPC is directly associated with the DNA degradation extension [120] and negatively correlated with the minimum inhibitory concentration (MIC) [15]. Interestingly, a study compared the TPC values among Australian honeys and identified greater values for _Calothammus_ spp. (red bell) honey and _Eucalyptusptus marginata_ (jarrah) honey when compared to the previously reported manuka honey, which is commonly stated to have greater antioxidant activity [121]. Similarly, a study compared Kazakhstan honeys and found that despite sunflower honey having a low TPC, high bactericidal activity was observed against MRSA [122].  
These findings suggest that the phenolic content is not the major non-peroxidant antimicrobial factor in honey and that this antimicrobial activity might depend more on the polyphenols' composition than on their quantity [122]. Therefore, different phenolic compounds can confer different antibacterial characteristics to honey. For instance, caffeicacid was reported to induce oxidative stress [123], whereas ferulic acid is more related to cell membrane damage, changing the cellular morphology [124]. Finally, gallic acid is also reported to compromise the cell membrane, leading to irreversible changes in its structure, as well as inducing pore formation [125]. Conversely, the compounds _t_-cinnamic acid, luminichrome, _o_-anisic acid, and eudesmic acid were associated with non-exertional antioxidant activity due to the lack of hydroxyl groups in their benzene ring [121].