**5. Natural products and endophytic fungi**

*Antimicrobial Resistance - A One Health Perspective*

successful activation of secondary metabolism.

*S. aureus*, *S. enterica*, and *S. flexneri*.

In this context, cultured actinobacteria combined with mycolic acid-containing bacteria (*Rhodococcus erythropolis*, *Dietzia* spp., *Nocardia* spp., *Williamsia* spp., *Gordonia* spp., *Mycobacterium* spp., and *Corynebacterium* spp.) has been a useful approach for the discovery of antimicrobial natural products [99, 101–103]. However, [102] suggests that mycolic acid is insufficient to activate these cryptic genes in *Streptomyces lividans* under monoculture conditions. According to the report, the direct attachment of *S. lividans* cells on the mycolic acid-containing bacteria is crucial for the

(A) *Antifungal activity produced by the endophytic Streptomyces sp. during the isolation.* (B–D) *Diversity of* 

Caraballo-Rodríguez [3] tested the endophytic actinobacteria *Streptomyces cattleya* RLe1, *S. mobaraensis* RLe3, *S. albospinus* RLe7, *Streptomyces* sp. RLe9 and *Kytasatospora cystarginea* RLe10 co-cultured with endophytic fungi *Coniochaeta* sp. FLe4 and *Colletotrichum boninense* isolated from the Brazilian medicinal plant *Lychnophora ericoides*. The authors identified the broad-spectrum angucycline derived from *S. mobaraensis* and two molecules produced by endophytic fungi. As already mentioned, the process of antibiotic resistance is spreading rapidly in relation to the discovery of new compounds and their introduction into clinical practice. The CDC classifies pathogens such as *B. anthracis* as biohazard category A, whose infection is fatal, and the symptoms may be similar to a common cold [104]. The preliminary study by [105] involved the isolation of the endophytic and rhizospheric microbiome associated with the medicinal plant *Polygala* sp. Natural products extracts produced by rhizoplane-derived actinomycetes showed potent inhibition against *A. baumannii*, *B. anthracis*, *E. coli* CFT073, *L. monocytogenes*, MR

*Caryocar brasiliense*, known as Pequi, is a tree native to the Brazilian savannah and commonly used in folk medicine. Bioactive substances such as gallic acid, quinic acid, ellagic acid, glucogalin, and corilagin were found in its extracts. In addition, they show a growth inhibition rate of the phytopathogenic *Alternaria solani* [106]. A rhizospheric strain of *Streptomyces* sp. was isolated from *C. brasiliense*, whose crude extract obtained from the axenic cultivation was able to inhibit *C. albicans*; in contrast, the co-cultured *Streptomyces* sp. extract increased the growth

of *C. albicans* in 50% and promoted the inhibition of *S. aureus* [107].

**82**

**Figure 3.**

*rhizospheric streptomycete colonies.*

The scientific interest in fungal natural products gained notoriety after the paclitaxel discovery [108]. Endophytic fungi exhibit the ability to synthesize plant-derived compounds by mimicking the metabolic pathways of the host plant, which confers multifaceted applications in the fields of agriculture, medicine, and pharmaceuticals [109].

The medicinal plant barbatimão (*Stryphnodendron adstringens*) has healing properties, antimicrobial, antioxidant, and anti-inflammatory activities, and its bark has a rich tannin-content [107, 110]. The study by [111] investigated the antimicrobial and anticancer activities of several fungi isolated from *S. adstringens*. The extract of *Nigrospora oryzae* promoted antifungal activity and inhibited the growth of *C. albicans* and *C. sphaerospermum*, while the extracts of *Diaporthe phaseolorum* and *Xylaria* spp. presented anticancer activities.

Although toxic to humans and animals, mycotoxins are secondary metabolites known for their cytotoxic effect against malignant cells [112]. Several species of *Fusarium* and *Beauveria bassiana* are skilled producers of mycotoxins, such as Beauvericin, which promote apoptosis in mammalian cells and exhibit insecticidal properties [113, 114], while Ochratoxin A is produced by some species of fungi, such as *Aspergillus* spp. and *Penicillium* spp. [115, 116].

The superbug methicillin-resistant *Staphylococcus aureus* is responsible for higher mortality rates in the community and hospital-acquired infections [117] due to its ability to resist multiple classes of antibiotics [118, 119]. In this context, fungal alkaloids are known for their potent antibacterial, anticancer, antiparasitic, and insecticidal activities [120]. In [121], a novel alkaloid compound, GKK1032C, is reported, which is produced by *Penicillium* sp. endophytically associated with the mangrove plant, exhibiting potent activity against methicillin-resistant *S. aureus*.

Saponins exhibit a wide range of biological activities, such as antifungal, hemolytic, antiviral, and immunomodulatory. These compounds represent an alternative to overcome multidrug-resistant microorganisms since they can act synergistically with antibiotics. Moreover, medicines that were once considered ineffective due to resistance problems might be effective for resistant microbes [122, 123]. Nevertheless, as reported by [124], saponin from *Quillaja saponaria* bark did not present synergistic activity in combination with ampicillin, streptomycin, and ciprofloxacin against a clinical strain of *E. coli*. In a short communication from [125], the isolation of triterpenoid saponins produced by the endophytic fungi *Fusarium oxysporum* and *Aspergillus niger* isolated from *Panax notoginseng* was reported. According to the authors, saponin extracts exhibited moderate to high antimicrobial activity against the pathogens tested.

## **6. Concluding remarks**

Antibiotic-resistant microbes represent a severe threat to the public health system worldwide. Furthermore, multidrug-resistant 'ESKAPE' organisms (*Enterococcus* spp., *Staphylococcus aureus*, *Klebsiella* spp., *Acinetobacter baumannii*, *Pseudomonas aeruginosa* and *Enterobacter* spp) are strictly associated with high rates of morbidity and mortality, as well as an economic impact.

In this chapter, we highlighted the strategies of antimicrobial drug discovery produced by endophytes and rhizospheric microorganisms, since enormous untapped resources remain. The use of such microbes in biotechnological processes has increased in recent years, as they are skilled producers of natural bioactive products that can be used as pharmaceuticals to face this ever-increasing threat.
