**2. Endophytes: an overview**

*Antimicrobial Resistance - A One Health Perspective*

The CDC (Centers for Disease Control and Prevention) has recognized the emerging antibiotic resistance as a significant threat to public health [8]. Superbugs, such as Methicillin-resistant *Staphylococcus aureus* (MRSA), show antibiotic resistance rates that surpass 50% in 5 out of 6 world regions; in contrast, the multidrugresistant *Acinetobacter baumannii*, described as a dangerous agent by the Society of Infectious Diseases of America (SIDA), is a notable threat in intensive care units (ICUs) due to the development of resistance to broad-spectrum antibiotics [5, 8–10]. Therefore, the search for compounds and the exploration of niches that harbor microorganisms that produce bioactive metabolites are critically important [11–13]. Several studies have shown that plant tissues represent a rich source of natural products for pharmaceutical and biotechnological interest. Most of these compounds are produced by microorganisms that live in intimate interaction with the host plant without causing damage; therefore, they are known as endophytes

*Timeline of antibiotic discovery that shows no new classes of antibiotics between the years 1962 and 2000* 

In the same context, the rhizosphere's microbiome can exert profound direct and indirect effects on plant growth, nutrition, and health in natural ecosystems. Its micro-community (bacteria, oomycetes, viruses, archeas, fungi and arbuscular mycorrhizae) is attracted and fed by nutrients, exudates, border cells and mucilage

Relevant studies have reported potent antimicrobial compounds, such as teixobactin, isolated from the non-cultivable bacterium *Eleftheria terrae* [17]. According to the authors in [17], teixobactin inhibits cell wall synthesis by binding to the highly conserved region of lipid precursors of peptidoglycan and teichoic acid. In addition, *S. aureus* and *Mycobacterium tuberculosis* did not develop resistance

In the study by [18], endophytic fungi were isolated from the medicinal plant *Orthosiphon stamineus*, where 92% of them exhibited significant inhibitory activity

*Paenibacillus polymyxa* can be found in several habitats. Its characteristic metabolism and production of substances enhance biotechnological applications based on the production of bioactive molecules. It is also widely applied in commercial agriculture as a bio-fertilizer grow plant promoter, biological control, and environmental remediation. In [19], *P. polymyxa* was endophytically isolated from *Prunus* spp., and the author reported the isolation of molecules which potently inhibited

against different species of bacterial pathogens and filamentous fungi.

**74**

[11, 14, 15].

**Figure 1.**

*adapted from: [6, 7].*

to teixobactin.

*S. aureus* and *E. coli*.

that are released by the root of the plant [16].

In 1866, de Bary outlined the first distinction between endophytes and plant pathogens. These microorganisms (typically fungi or bacteria) colonize the plant's internal tissues and live part of its life or its entire life cycle without causing apparent damage, establishing a mutualistic interaction with the host plant. Moreover, endophytes are capable of producing beneficial substances, such as alkaloids, enzymes, antibiotics and other compounds that protect and help the plant under stress conditions in exchange for nutrients and protection provided by the host plant [14, 15, 20–22].

In this context, plants have served humanity for centuries and led to the discovery of novel bioactive compounds. However, concerns regarding biodiversity and conservation, as well as large quantities of plant tissue, are required to produce sufficient yields of compounds [23]. According to [24], paclitaxel isolation requires about 10,000 kg of *T. brevifolia* bark to yield 1 kg. On the other hand, several studies have shown that endophytes may produce similar or even the same bioactive compounds as their plant hosts [20, 23, 25].

Fungi are skilled producers of natural products, including antitumor agents, cholesterol-lowering agents, immunosuppressants and antibiotics [25, 26]. The study by [27] detected potent antimicrobial properties of the natural product extract (NPE) of endophytic fungi associated with *Myrciaria floribunda*, *Alchornea castaneifolia* and *Eugenia aff. Bimarginata* against several pathogens. The methanolic extracts presented MIC values ranging from 7.8 to 1000 μg/mL against *C. krusei*, *C. parapsilosis*, *C. neoformans*, *C. albicans*, and *C. glabrata*. The inhibition of *S. aureus* and *B. cereus* ranged from 7.8 to >1000 μg/mL. Also, endophytic fungi were isolated from *Cinnamomum mercadoi*, a medicinal tree endemic to the Philippines. The ethyl acetate extract of *Fusarium* sp. presented moderate inhibition against *E. coli*, *E. aerogenes*, *S. aureus*, and *B. cereus* with minimum inhibitory concentrations of 2.1, 4.2, 4.2, and 3.8 mg/mL, respectively [28].

Therefore, the emerging use of endophytes in the research and development of new drugs represents the most successful example of bioactive natural products in medicine, pharmaceutical and biotechnological applications. **Table 1** provides an idea of some secondary metabolites of endophytic fungi and bacteria tested against resistant and multidrug-resistant microorganisms.
