# Propolis as Natural Product in the Oral Cavity Bacterial Infections Treatment: A Systematic Review
## 3 Antibacterial Properties of Propolis: Mode of Action
Quercetin, morin, luteolin, and rutin inhibit efflux pumps such as ATP-binding cassette (ABC) transporter, multi-antimicrobial and toxic compound extrusion (MATE) transporter, major facilitator MFS) transporter, small multidrug resistance (SMR) transporter, and resistance-modulation cell division (RND) transporter, leading to the decreased level of inhibitory concentration [54]. The inhibition of protein synthesis is possible by the inhibition of RNA-polymerase, modulation of the crosstalk through the Toll-like receptor (TLR) of host-microbiota by flavonoids, and activating different chief protein kinases by flavonoids [55]. Apigenin,catechin, quercetin, morin, and naringenin can cause cell membrane disruption and leakage of intracellular contents [54]. Flavonoids (flavanols, flavan-3-ols, and flavones) bind to topoisomerase II, resulting in cleavage of the DNA [54]. The inhibition of nucleic acid synthesis is possible by binding to (I) the bacterial DNA gyrase B subunit, (II) topoisomerase II as well as inhibition of (III) topoisomerase IV-dependent deactivation activity, (IV) dihydrofolate reductase (DHFR) and (V) helicase. Quercetin, ellagic acid, and apigenin bind to the bacterial DNA gyrase B subunit to inhibit ATPases activity and decrease bacterial activity [54,55]. Luteolin, morin, and myricetin inhibit helicase, while epigallocatechin-3-gallate (ECGC) inhibits dihydrofolate reductase (DHFR), which results in inhibiting the synthesis of nucleic acid and reducing the growth of bacteria [54]. Flavonoids may also inhibit bacterial motility because they \"quickly arrest bacterial movement by blocking swarming motility to prevent bacterial adhesion as well as colonization because bacterial movement and attachment occur at different times\" [54]. It is also believed that bee glue \"wraps\" around bacteria, leading to their elimination by the body's immune system. The strong immune and inflammatory response may be stimulated by flavonoids, which are very potent inhibitors of eicosanoids production [46]. The anti-inflammatory mechanisms of propolis include the inhibition of cyclooxygenase-genase (COX) and subsequent inhibiting biosynthesis of prostaglandandins, and free radical scavenging. Additionally, nitric oxide synthesis is inhibited, the concentration of inflammatory cytokines is reduced, and immunosuppressive effects are observed [52]. Artepillin C possesses anti-inflammatory activity such as the modulation of NF-\(\kappa\)B and inhibition of prostaglandin E2 and nitric oxide [49]. Caffeic acid phenethyl ester inhibits the activity and expression of COX-2, while pinocembrin treatment of mice significantly reduces neuronal pro-inflammatory cytokines (TNF-\(\alpha\), IL-1, and IL-6), chemokines (intercellular adhesion molecule-1, vascular cell adhesion molecule-1), inducible nitric oxide synthase (iNOS), and aquaporin-4. Moreover, pinocembrin suppresses the nuclear translocation of NF-\(\kappa\)B and decreases TNF-\(\alpha\) expression [52]. The summarized antimicrobial properties of propolis are presented in Figure 2.