Plant Derived Natural Products against Pseudomonas aeruginosa and Staphylococcus aureus: Antibiofilm Activity and Molecular Mechanisms

Abstract

Bacteria are social organisms able to build complex structures, such as biofilms, that are highly organized surface-associated communities of microorganisms, encased within a self- produced extracellular matrix. Biofilm is commonly associated with many health problems since its formation increases resistance to antibiotics and antimicrobial agents, as in the case of Pseudomonas aeruginosa and Staphylococcus aureus, two human pathogens causing major concern. P. aeruginosa is responsible for severe nosocomial infections, the most frequent of which is ventilator-associated pneumonia, while S. aureus causes several problems, like skin infections, septic arthritis, and endocarditis, to name just a few. Literature data suggest that natural products from plants, bacteria, fungi, and marine organisms have proven to be effective as anti-biofilm agents, inhibiting the formation of the polymer matrix, suppressing cell adhesion and attachment, and decreasing the virulence factors' production, thereby blocking the quorum sensing network. Here, we focus on plant derived chemicals, and provide an updated literature review on the anti-biofilm properties of terpenes, flavonoids, alkaloids, and phenolic compounds. Moreover, whenever information is available, we also report the mechanisms of action.

Keywords: Pseudomonas aeruginosa; Staphylococcus aureus; antibiotic-resistance; biofilm; flavonoids; plant-derived natural products; quorum sensing; terpenes.

Figure 1

The three major Pseudomonas aeruginosa QS systems with their main effects. (1) LasI produces 3-oxo-C12-HSL, which acts on LasR. This leads to induction of aprA, lasA, las B, and toxA genes and other virulence genes that are under its regulation. (2) RhlI produces C4-HSL, that acts on RhlR, which induces phz, lasA, rpoS, lasB, rhlAB, and hcnABC gene expression. (3) PqsABCDH produces HHQ that acts on PqsR, regulating the gene expression of LecA, Phz, Hcn, and rhl. Additionally, LasR positively regulates 2-heptyl-1H-quinolin-4-one (HHQ) through the complex LasR-3-Oxo-C12-HSL on PqsH. LasR positively regulates rhlR, again through the complex LasR-3-oxo-C12-HSL and rhII. Finally, LasR positively regulates HHQ through PqsE. Elastase and protease exert their effect on disruption of the epithelial barrier and matrix protein (collagen, elastin, etc.). ToxinA induces cell death favoring the establishment of infection and colonization. The alkaline protease is involved in degradation of the host complement system and cytokines, playing a role in immune evasion and persistent colonization. Rhamnolipids favor immune evasion and biofilm formation. Hydrogen cyanide reduces lung function. Pyocyanin, among various effects, causes oxidative stress and, like lectinA, induces paralysis of airway cilia. RpoS is a negative transcriptional regulator of rhlI.

Figure 2

The Agr quorum sensing (QS) system in Staphylococcus spp. The Agr locus comprises two divergent transcriptional units, RNAII and RNAIII, containing genes responsible for the production of many virulence factors in S.aureus. AgrD encodes the precursor of AIP, which is then processed and transported through AgrB. The processed AIP interacts with a histidine sensor kinase receptor AgrC, which in turn leads to the phosphorylation (*P) of AgrA. This leads to the activation of the regulator AgrA, which binds to the chromosomal P2 and P3 promoter regions to upregulate transcription of RNAII and RNAIII. RNAIII can induce upregulation of virulence factor expression as proteases, toxins, and degradative enzymes.

Figure 3

Chemical structures of compounds containing nitrogen, organosulfur compounds, and terpenoids active against P. aeruginosa.

Figure 4

Chemical structures of flavonoids and other phenolic compounds active against P. aeruginosa.

Figure 5

Chemical structures of terpenoids active against Staphylococcus aureus.

Figure 6

Chemical structures of flavonoids active against S. aureus.