# Endowed Polyphenols in Advanced Delivery Systems for Vaginal Infections
## 6 Polyphenols as Antimicrobial Agents  
Over the last 70 years, antibiotics have proven to be valuable drugs in treating bacterial infections [83]. However, their great availability has caused a general misuse, most commonly, extensive and unregulated use. This behavior, in turn, has given rise to new strains of multi-drug-resistant organisms (MDR), more problematic than the original ones [84]. These include methicillin-resistant _S. aureus_ (MRSA), whose incidence in US intensive care units rose from 2% in 1974 to 64% in 2008 [85]. Regarding multi-drug-resistant _E. coli_, in a 2012 study, MDR was present in 92.2% of _E. coli_ (\(n=232\)) isolates from Khartoum state, Sudan [86]; in a previous study in 2000, it was 58% [87]. This bacterial resistance normally occurs by genomic mutation or through the acquisition of new genetic information that encodes resistance elements [84]. Almost 20 years after the discovery of penicillin, 50% of all _S. aureus_ were penicillin-resistant, and around 10 years later, that number rose to almost 80%. Methicillin was released in 1960, and only one year later, the first strains of MRSA were discovered [88, 89]. Clindamycin, an antibiotic used to treat BV, has been shown to create a path for clindamycin-resistant anaerobic bacteria; in a study performed on 48 women, from whom 1059 anaerobic bacteria isolates were obtained, 53% of these demonstrated resistance after therapy [90]. Thus, with an ever-growing concern over antibiotic-resistant microorganisms, the scientific community started researching new compounds with antimicrobial activity. Plant extracts have been part of human health for centuries, with the earliest findings of the use of medical plants dating up to 4000 B.C. Although these medicines may be efficient for the treatment of diseases such as urinary tract infections (e.g., _Arctostaphylos uvaursi_) and tuberculosis infections (e.g., oils of _Hydrastis canadensis_), very few are regulated as antimicrobials [84]. Plants, when under stress, on tissue disruption or pathogen attack, produce various phytochemical compounds as a defense mechanism. These secondary metabolites include \begin{table}
\begin{tabular}{c c c c c} \hline \hline
**Active Ingredient** & **Indications** & **Dosage Form** & **Mechanism of Action** & **Reference** \\ \hline Fluconazole & Recurrent VVC & Oral Tablet & Inhibits ergosterol synthesis, leading to fungal cell death. & [68, 69] \\ Butoconazole & VVC & Cream & Inhibits fungal cell membrane ergosterol & [70, 71] \\  & & & production, disrupting fungal growth. & [72, 73] \\ \hline Nystatin & VVC & Vaginal Tablet, Cream & Binds to sterols in the fungal cell membrane, causing leakage of cell contents. & [72, 73] \\ \hline Clindamycin & BV & Cream, Gel, Oral Tablet & Inhibits bacterial protein synthesis by binding to the 505 ribosomal subunit. & [74, 75] \\ \hline Boric Acid & Recurrent VVC & Vaginal Suppository & Acidifies the vaginal environment, making it hostile to fungal growth. & [76, 77] \\ \hline Estradiol/Conjugated & & & Restores vaginal tissue by increasing epithelial & [78, 79] \\ Estrogens & AV & Cream, Tablet, Ring & cell growth and pH balance. & [78, 79] \\ \hline \hline \end{tabular}
\end{table} 
Table 1: _Cont._photoalexins, polyphenols such as alkaloids, flavonoids, phenolic acids, and other products [84]. Polyphenols, or \"plant phenols\", are divided into many classes, with the main ones being phenolic acids, flavonoids, stilbenes, phenolic alcohols, and lignans [91]. Each of these classes has its base molecular structure and therefore its mechanism of action against microorganisms. These include binding to cell wall proteins, leading to loss of functions, enzyme inhibition, and interaction with substrates, leaving them unavailable to the microorganism, among other effects [92]. The number of plant species that exist and the number of plants to be described is not agreed upon, but speculations lie around 250,000-280,000 of the former and 50,000-70,000 of the latter [93].