**4. Translation to real-world scenario**

*Pistacia lentiscus* var. chia) is effective in killing *H. pylori* [67]. This antibacterial effect was attributed to their rich composition in oleanolic acid, isomasticadienolic acid, masticadienolic, and moronic acid [67]. Paraschos et al. demonstrated that the prophylactic treatment with the TMEWP was not able to prevent *H. pylori* infection in C57BL/6 mice infected with mouseadapted *H. pylori* SS1 strain [67]. Nevertheless, the number of *H. pylori* colonies significantly reduced (1.5 log colony forming units/g of tissue) when the animals were subjected to continuous administration of 0.75 mg of TMEWP for 3 months [67]. Shin et al. reported that betulinic acid and oleanolic acid, extracted from *Fosythia suspensa*, were able to inhibit the urease activity of *H. pylori* ATCC 43504 [68]. Furthermore, Parreira et al. reported that outer bark extracts of *Eucalyptus nitens* and *E. globulus*, rich in betulinic, betulonic, oleanolic, and ursolic acids (**Figure 4**), have anti-*H. pylori* activity against strains with distinct virulence degree [69]. Interestingly, the eucalyptus extracts had a lower minimal inhibitory concentration than the isolated pure triterpenic acids, which led to the conclusion that the final observed antibacte-

Although not specifically designed toward *H. pylori* infection, different strategies to improve the oral bioavailability of triterpenic acids have been studied. For example, oleanolic acid bioavailability has been enhanced by using a phospholipids complex with hydroxyapatite [70]. Yang et al. have developed liposomes to increase ursolic acid bioavaliabitliy [71] and pharmacokinetic studies carried out by Ge et al. reported that the oral bioavailability of ursolic acid was 27.5-fold higher when it was incorporated in nanoparticles than when administered as a

The abovementioned advances in increasing the bioavailability of triterpenic acids using bioengineering strategies will enable, in the near future, to further pursue research of novel

**Figure 4.** Chemical structures of triterpenic acids: betulinic (BA), betulonic (BOA), oleanolic (OA), and ursolic (UA) acids.

nonantibiotic and more effective "nature-inspired" therapies against *H. pylori*.

rial effect was due to synergic effects [69].

116 Helicobacter Pylori - New Approaches of an Old Human Microorganism

free compound [72].

Both fatty acids and triterpenic acids have been reported to exhibit similar performance against *H. pylori*. Nevertheless, their action mechanisms are fairly distinct: while fatty acids are reported to interact with the bacterial membrane, triterpenic acids are reported to be more involved in enzymatic inhibition, namely urease hindering [5]. Since both bioactives classes target crucial structures for *H. pylori* survival, emergence of resistance is not anticipated, as it would require massive bacterial energy [32, 69].

Despite the remarkable effects associated to fatty and triterpenic acids for gastric infection management, translation into real-world applications is still delayed. For that, it has contributed the fact that only in the last decade more attention has been paid to nature-derived molecules, counteracting the "chemical pharmacological" tendency that had been initiated in the beginning of the twentieth century. Also, there was a significant reduction of investment in the clinical development of antibiotics over the last years. In fact, only 1.6% of the drugs under clinical development by the world's largest drug companies are antibiotics [73]. This has boosted the search for other sources of antimicrobials. In addition, bioengineering emerged in the twenty-first century as a powerful tool to develop drug delivery systems and, consequently, to overcome the more generalized drawbacks associated with the lipophilic bioactive compounds discussed in this chapter [5]. Bioengineering approaches for fatty acids specific application against *H. pylori* are already on a "fast-track," while those for triterpenic acids are only now evolving, which explains the lack of solid studies coupling these bioactives with bioengineering strategies.

To the date and to the best of our knowledge, most of the herein described compounds are in *in vivo* studies phase, being expected that in the next few years some will cross the clinical trials barrier. There are several factors contributing to the anticipated success of these "naturebased" strategies. They are generally cost-effective, due to their abundance in nature, and they require low-cost extraction productions. Furthermore, the biotechnological improvements that include nanotechnological coupling to nature-derived molecules will hopefully contribute to reaching "real-life" applications. In addition, more "nature-based" molecules are reaching the market with FDA approval to treat infectious disease, such as antimalaria Artemisinin therapies, based on an herb employed in Chinese traditional medicine [74], which anticipates the future success of nature-inspired strategies for *H. pylori* eradication.

#### **5. Conclusion**

*H. pylori* infection is one of the most prevalent infections worldwide, which is also reflected onto the high prevalence of gastric cancer. Emerging antibiotic resistance leads to an urgent need of alternative treatments. Resourcing to widely available lipophilic natural bioactive compounds with anti-*H. pylori* activity, namely fatty or triterpenic acids, should be further considered as novel therapeutic options. In this context, nanotechnology emerges as a key player, as it allows overcoming the bioactive major drawbacks that have been holding back their "real-world" application.
