Unlocking the Potential of Brazilian Plant Terpenes to Combat Antimicrobial Resistance

Abstract

The group of bacteria known as ESKAPE: Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter spp. are well recognized for their high virulence and pathogenicity, employing diverse modalities and mechanisms to resist multiple classes of clinically relevant antibiotics. Their capacity to evade treatment presents a major public health challenge, highlighting the urgent need for novel antibiotics to address the growing resistance crisis. The plant kingdom presents a promising avenue to this fight. Plants are naturally endowed with the genomic and proteomic machinery to synthesize a wide arsenal of secondary metabolites, including terpenes and terpenoids, which have demonstrated potent antimicrobial properties both as standalone agents and as synergists or enhancers of existing antibiotics. These plant-derived compounds often operate through mechanisms distinct from those of conventional antibiotics, offering a potentially effective solution against antibiotic-resistant bacteria. Brazil, home to some of the richest biodiversity on the planet, boasts 46,000 recorded plant species, with 250 new species identified annually. This review delves into the methods of preparing and isolating terpenes and terpenoids from plants, explores the techniques used to assess their antibacterial activity, and highlights ongoing research using Brazilian plants to target ESKAPE pathogens. This compilation of knowledge aims to establish a pipeline for evaluating the antibacterial potential of terpenes and terpenoids, contributing to efforts addressing the growing threat of antimicrobial resistance.

Keywords: Antibiotic Resistance; Antimicrobial Activity; Brazilian Medicinal Plants; ESKAPE Pathogens; Essential Oils; Extraction Methods; Phytochemical Exploration; Secondary Metabolites; Terpenes; Terpenoids.

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Structures of the terpenes. Terpenes are hydrocarbons with significant structural variations, including cyclic and acyclic skeletons, with a backbone composed of five-carbon isoprene units (C₅H₈). Terpenes are classified according to the number of the isoprenoid units as monoterpenes, diterpenes, triterpenes, tetraterpenes, or polyterpenes.

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Biosynthetic pathways for terpenes in plants: the MVA pathway (left) occurs in the cytoplasm and endoplasmic reticulum (ER), and the MPE pathway (right) occurs in plastids. Abbreviations (in order of appearance from left to right): AACT, acetoacetyl-CoA thiolase; HMGS, 3-hydroxy-3-methylglutaryl-CoA synthase; HMGR, 3-hydroxy-3-methylglutaryl-CoA reductase; MVA, mevalonic acid; MK, mevalonate kinase; MVAP, mevalonate 5-phosphate; PMK, phosphomevalonate kinase; MVAPP, mevalonate diphosphate; MDD, mevalonate diphosphate decarboxylase; IDI, isopentenyl diphosphate isomerase; IPP, isopentenyl diphosphate; DMAPP, dimethylallyl diphosphate; FPPS, farnesyl diphosphate synthase; FPP, farnesyl diphosphate; GA-3P, d-glyceraldehyde 3-phosphate; DXS, 1-deoxy-d-xylulose 5-phosphate synthase; DXR, 1-deoxy-d-xylulose 5-phosphate reductoisomerase; MEP, 2-C-methylerythritol 4-phosphate; MCT, 2-C-methyl-d-erythritol 4-phosphate cytidylyltransferase; CMK, 4-(cytidine 5′-diphospho)-2-C-methyl-d-erythritol kinase; MDS, 2-C-methyl-d-erythritol 2,4-cyclodiphosphate synthase; HDS, (E)-4-hydroxy-3-methylbut-2-enyl diphosphate synthase; HDR, (E)-4-hydroxy-3-methylbut-2-enyl diphosphate reductase; GGPPS, geranyl Mapp diphosphate synthase; GPPS, geranyl diphosphate synthase; GPPP, geranylgeranyl diphosphate; GPP, geranyl diphosphate.

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Isolation, identification, and downstream analyses of the bioactive compounds. In general, the process of obtaining terpenes from plants for medicinal use involves the following steps: selection of the appropriate biological material from plants (leaves, bark, roots, fruits, etc.); disruption of plant cells to liberate their chemical components via dry or wet methods; extraction of the bioactive compounds by employing an appropriate solvent, or through methods like distillation or compound trapping, the target compound(s) can be isolated from the biological extract using chromatographic techniques. Finally, the isolated compound(s) can be identified and used in downstream analyses.