Review Articles | Volume 12, Issue 4, July, 2024

Quorum sensing inhibition activities of Philippine ethnobotanicals against multidrug-resistant pathogens

Khristina G. Judan Cruz   

Open Access   

Published:  May 20, 2024

DOI: 10.7324/JABB.2024.164825
Abstract

Alternative therapeutic approaches to target microbial multidrug resistance (MDR) have become an important thrust in research. One potential approach to manage antibiotic resistance and pathogenicity in MDR pathogens is through targeting quorum sensing (QS). Blocking the QS system does not affect bacterial growth while preventing bacteria from triggering virulence, reducing pathogenicity and selective pressure to survive, hence, reducing the resistance evolution. Recent ethnopharmacological research highlights the prospects of Philippine ethnobotanicals to discover novel molecules and approaches for targeting the QS system to control diseases and pathogens. In this review, two sets of Philippine ethnobotanicals utilized by ethnic communities - Ikalahan and Ilongot-E?ongot – are highlighted as QS inhibitors. Inhibition of QS-linked virulence factor production such as violacein, biofilm, DNase, α-Hemolysin, swarming motility and coagulase in MDR pathogens Pseudomonas aeruginosa, Staphylococcus aureus, Aeromonas hydrophila, Streptococcus agalactiae, Candida albicans and one QS reporter bacteria, Chromobacterium violaceum by the ethnobotanical extracts are presented. All Philippine ethnobotanicals from the two ethnic communities included in this review showed inhibition on one or more virulence factors highlighting their activities against QS and emphasizes their potential for in-depth research on QS-based drug development for antipathogenesis.


Keyword:     Ethnobotanicals Quorum sensing Virulence factors


Citation:

Cruz KGJ. Quorum sensing inhibition activities of Philippine ethnobotanicals against multidrug-resistant pathogens. J App Biol Biotech. 2024;12(4):1-13. http://doi.org/10.7324/JABB.2024.164825

Copyright: Author(s). This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike license.

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1. INTRODUCTION

The global emergence of antimicrobial resistance (AMR) has become a serious health concern. Recent statistics reported AMR as the direct cause of 1.27 million deaths in 2019 with almost 5 million deaths due to complications of AMR [1], and these numbers are likely to intensify in the coming years. Aside from presenting urgent health concerns and high mortality rates, antimicrobial resistance has imposed major economic burdens on the world healthcare system with global economic impacts due to increasing treatment and diagnostic costs. It is foreseen that the global gross domestic product will decline by 3.8% and will lose $100 trillion by 2050 if the AMR crisis is not managed [2,3]. Multi-drug resistance (MDR) microbes have emerged as a result of persistent and prolonged antibiotic treatment and have become less responsive to commercial antibiotics. As antibiotics become less effective while more MDR pathogens emerge and spread globally, research efforts are urgently needed to produce novel, effective strategies to control antimicrobial resistance.

A potential alternative to manage antibiotic resistance and pathogenicity in MDR pathogens is through targeting quorum sensing (QS). QS is a communication system in microbes to coordinate metabolic activities for adaptation to environmental conditions through the regulation of specific genes [4,5]. This is made possible by the production and release of signal molecules called autoinducers [6,7] followed by a cascade of transcription regulation and gene expression through intricate signaling pathways [8]. This system is density-dependent, that is, the bacterial population must reach a threshold density to collectively alter gene expression patterns [9]. QS controls several physiological processes and virulence factors that enhance disease progression more effectively, and these include bioluminescence, biofilm formation, swarming motility, coagulase, and competence [10-12]. QS has attracted considerable interest as a mechanism in controlling pathogenesis in microbes as QS can be selectively blocked to control virulence. Blocking the QS system, called QS inhibition (QSI), does not affect bacterial growth while preventing bacteria from triggering virulence, thereby reducing pathogenicity. In this approach, bacteria are not exposed to selective pressure to survive, hence reducing the resistance evolution [13,14]. QSI represents a novel strategy to control pathogenic infections [15] and several studies have succeeded in demonstrating significant outcomes in terms of practical applicability. This suggests that QSI is a practical alternative to antibiotics [16].

Advancing trends in the control of antimicrobial resistance call for innovative and practical alternatives based on biological control approaches. Recent ethnopharmacological research highlights the potential of ethnobotanicals to discover novel molecules and approaches to control diseases and pathogens. Ethnobotanicals are plants of cultural and traditional significance, particularly in relation to their use by the ethnic community for a wide range of purposes [17,18]. Ethnobotany explores how ethnic cultures interact with and utilize these plant resources [19]. Ethnological practices are conventionally handed down through generations as traditions, and this includes medicinal practices using plants to manage diseases and ailments. Most ethnobotanicals are collected from the wild, mostly from geographically isolated areas, and as such, many remain untapped for their pharmacological prospects. This presents valuable resources for discovering and developing pharmacological strategies against microbial resistance and pathogenesis.

Plants and plant metabolites have shown actions on animal and microbial cells and displayed remarkable efficiency against a wide range of medical conditions. Through co-evolution with bacteria, plants developed an array of defenses through metabolites to protect themselves against infections. These antimicrobial metabolites have been shown to inhibit several pathogenic mechanisms in microbes. Phytochemicals have been proven to block QS systems by interfering with QS signals reducing their capacity to coordinate activities resulting in decreased virulence and pathogenicity [20]. Plant metabolites either resemble or mimic QS signals in bacteria that affect QS-related activities making this one of the most effective natural suppressors of QS communication systems [21].

The Philippines is a mega-biodiverse country that hosts two-thirds of the global biodiversity with around 80% of the world’s plant and animal species. Despite its small size, the Philippines harbors higher biodiversity than any other country in the world. In terms of plant species, it ranks 5th in the world and hosts 5% of the world’s flora [22]. The Philippines comprises an archipelago of more than 7000 islands. Its geography contributed to the country’s exceptional level of endemism including at least 25 genera of plants and 50% terrestrial wildlife species. Half of the 52,177 described species in the Philippines are endemic making it one of the top ten most endemic countries in the world [23]. Despite being a top biodiversity hotspot in the world, new species are still being discovered. Medicinal plants and their metabolites played a key role and continue to provide a vast resource for diverse applications in pharmacotherapy in modern medicine [24-26]. Scientific validation of unexplored medicinal plants is now critical due to the fast rate of habitat degradation.

The ethnobotanicals – the plants used by ethnic communities – constitute a rich and expansive source of plants for the discovery of new antipathogenic drugs. The Philippines hosts diverse ethno-linguistic groups with unique customs and cultures [27]. Their cultures and traditions are inextricably linked to their lands which they consider pure and sacred [28]. One of their notable customs is the use of ethnomedicinal plants that are usually found within their ancestral domains. These ethnic communities typically inhabit geographically isolated areas, and hence, most ethnobotanical species still have untapped pharmacological potential. Among these ethnic groups are the Ilongots and the Ikalahans. The Ilongot indigenous people comprise a major ethnic group in the Philippines. Their communities live mostly in the mountains of the provinces of Quirino, Aurora, and Nueva Vizcaya where plant biodiversity is high. There are five Ilongot subgroups, one of which is the E?ongots who mostly reside in Aurora Province. The Ilongot-E?ongot group has a deep knowledge of the vast resources of plants within their ancestral domain. Their practice of traditional medicine using these plants is handed down through generations which are still practiced in the modern era [29]. The Ikalahans, on the other hand, are indigenous people with ancestral domains in the north-east Philippines along the mountainous terrain of Cordillera and Caraballo which are mostly situated in altitudes of more than 3000 feet above sea level [30,31]. Their land is characterized by montane forests with a cool climate and heavy rainfall supporting high levels of biodiversity of approximately 1500 plant and animal species [30,32]. The Ikalahans are renowned for their environmentally sustainable ‘indigenous knowledge practice systems’ that are transferred, protected, and maintained through generations [30,32].

Parallel to the loss in biodiversity, indigenous knowledge of medicinal plants is also at risk of being lost due to modernization. There have been few ethnobotanical evaluations for scientific validation. Ethnobotanicals represents a contemporary collection of plants that have attracted attention as potential sources of antipathogenic compounds and demonstrates a promise of identifying potent, natural sources of QS inhibitors necessary for the development of safe, new antipathogenic therapies [33]. Several papers have reported the inhibition of QS pathways and virulence factors in bacteria and fungi using natural compounds [34-38]. Phytochemicals are natural QS inhibitors [39] and as such, bioactive molecules from ethnobotanicals can be promising alternatives to antibiotics. Ethnobotanicals offer a deep array of newly discovered bioactive molecules and are now contributing toward deeper, practical evidence-based approaches using traditional species. With the advancements in pharmacology, the development of several drugs can be attributed to discoveries in ethnobotany [40,41].

This review highlights the series of evaluations conducted to assess the potential of Philippine ethnobotanicals to control QS related virulence factors in MDR pathogens as well as the significant results of these evaluations. Two sets of Philippine ethnobotanicals of the following indigenous communities are included in this review: Ikalahans of Imugan, Nueva Vizcaya, Philippines, and the Ilongot-E?ongots of Maria Aurora, Aurora, Philippines. The ethnobotanicals of the Ikalahans tested were Ageratina adenophora, Alstonia scholaris, Ayapana triplinervis, Bidens pilosa, Cestrum nocturnum, Derris elliptica, Oreocnide trinervis, Pittosporum pentandrum, Sarcandra glabra, and Lipang daga (no known scientific name) [Table 1]. Three solvents were used for crude extraction in this group of ethnobotanicals: ethanol, methanol, and n-hexane. The Ilongot-E?ongot ethnobotanicals with local names and plant parts used in the evaluation were based on the survey by Balberona et al., 2017 [29]: Adenanthera intermedia, Ceiba pentandra, Cymbopogon winterianus, Dillenia philippinensis, Diplazium esculentum, Eleusine indica, Ficus sp., Hydrocotyle vulgaris, Hyptis suaveolens, Mikania micrantha, Premna odorata, Phyllanthus urinaria, Senna alata, Stachytarpeta jamaicensis, Urena lobata, and Talahib (no known scientific name) [Table 1]. Only ethanolic extracts of these plants were evaluated.

Table 1: Ethnobotanicals from 2 Philippine ethnic communities evaluated for anti-quorum sensing activities.

Philippine Ethnobotanicals

Ilongot-EgongotIkalahan


Scientific nameLocal nameScientific nameLocal name
Adenanthera intermediaKaresAgeratina adenophoraPanawel
Ceiba pentandraBétékAyapana triplinervisPantallion
Cymbopogon winterianusTadayAlstonia scholarisPalay
Dillenia philippinensisKatmonBidens pilosaAnwad
Diplazium esculentumPako-pakoCestrum nocturnumDama de noche
Eleusine indicaPagDerris ellipticaOpay
Ficus sp.BaleteOreocnide trinervisLal-latan
Hydrocotyle vulgarisGotu kolaPittosporum pentandrumLahwik
Hyptis suaveolensAmbabangotSarcandra glabraHag-ob
Mikania micranthaOla-olaLipang daga (no known scientific name)
Premna odorataAsédaong
Phyllanthus urinariaTaltalikod
Senna alataBensola
Stachytarpeta jamaicensisLuzviminda
Urena lobataPukot
Talahib (no known scientific name)

This paper reviews the QS inhibition properties of the ethnobotanicals against the pathogenic bacteria Pseudomonas aeruginosa [42-47], Staphylococcus aureus [48-52], Aeromonas hydrophila [33], and Streptococcus agalactiae [53]. The Ikalahan ethnobotanicals were also tested against the QS reporter bacteria Chromobacterium violaceum [54,55]. Inhibition of biofilm formation by the Ilongot-E?ongot ethnobotanicals against Candida albicans has been explored [56]. The test bacteria in the papers included in this review are drug-resistant bacteria that are responsible for a large number of infections in humans and constitute a serious threat to public health. P. aeruginosa and S. aureus form part of the ESKAPE pathogens which includes six MDR pathogens [57]. ESKAPE includes other bacterial pathogens such as Enterococcus faecium, Klebsiella pneumoniae, Acinetobacter baumannii, and Enterobacter spp. This group of pathogens comprise the leading cause of life-threatening nosocomial infections globally [58] that employ a wide spectrum of mechanisms to evade actions of antimicrobials that eventually lead to antibiotic resistance [59] and has been put as a key priority for new therapy development [3]. P. aeruginosa and S. aureus are both opportunistic pathogens responsible for a number of hospital-acquired infections worldwide [60-62]. Virulence factors of both pathogens are largely regulated through QS which facilitates the production of these factors in a coordinated, cell-density-dependent manner. P. aeruginosa biofilms largely contribute to lung infections by adhering to mucin in the respiratory tract [50,63]. Aside from biofilms, it possesses an array of virulence factors such as the production of toxins essential for penetrating tissues [64,65]. Aside from disease progression and host colonization, the armory of virulence factors plays a major role in the bacteria’s capability to adapt to environmental changes to rapidly evolve resistance to antibiotics [61]. QS regulates more than 10% of P. aeruginosa genes [66] that are primarily involved in virulence factor production, biofilm development, and other factors essential for colonization and disease progression such as the development of mechanisms for antibiotic resistance, motility and adjustment of pathways for metabolism [66-69]. A. hydrophila and S. agalactiae are significant fish pathogens where infections cause disease outbreaks and huge economic losses, particularly in intensive aquaculture productions where fish densities are high [70-74]. Both bacteria are also zoonotic agents [75-77] and have new emerging multidrug-resistant strains due to the heavy use of antibiotics in aquaculture. In Candida sp., surging antifungal resistance presents an emerging concern for the immediate development of control strategies [78,79]. C. albicans is one of the most prevalent nosocomial opportunistic commensals in humans [80] that is mainly linked to a number of infections such as candidiasis and bloodstream infections [81]. It possesses an array of strategies that are responsible for the emergence of its resistance to various classes of drugs with an alarming mortality rate of 40% in spite of antifungal treatments [82-84].

This review presents the QS inhibition activities of ethnobotanicals utilized by two major groups of ethnic communities in the Philippines [Table 1] in several virulence factors.


2. INHIBITION OF VIRULENCE FACTORS BY PHILIPPINE ETHNOBOTANICALS

2.1. Violacein Production

C. violaceum is a standard reporter bacterium often used to test quorum-sensing activities through the production of a purple-colored pigment violacein [85]. Violacein is a pigment required for swarming and formation of biofilm and is involved in the regulation of several virulence factors [86]. C. violaceum is also a significant human pathogen. Although not common, C. violaceum infections can cause high mortality rates [87,88] that are often due to multiorgan failure. C. violaceum infections are usually accompanied by pneumonia, severe sepsis, and septic shock [89].

Due to easy visualization, C. violaceum is routinely used to screen natural products for their QSI activities. Violacein is produced after the activation of QS through the mediation of acyl-homoserine lactone (AHL) signals [90]. Bacteria employ the AHL molecules as signals to regulate the expression of certain genes in response to the environment and population density that are recognized by specific receptors. Thus, through the visible inhibition of violacein production, it can be said that AHL signals are blocked. AHL signaling is not only required for violacein production in C. violaceum, but also critical for plant and animal diseases, specifically bacteria-caused infections. Blocking AHL signals can be tapped to control pathogen virulence [91].

The ethnobotanical extracts of the Ikalahans were evaluated for QSI by phenotypic visualization of violacein production reduction in C. violaceum through the standard disk diffusion assay. Two solvents – ethanol and methanol – were used for the extraction of plants. The ethanolic and methanolic extracts of S. glabra, D. elliptica, A. adenophora, and A. triplinervis visibly showed consistent inhibition of the production of the purple pigment [54,55] [Table 2] as shown by the absence of growth around the disc. In addition, the absence of violacein production was also noted in bacterial cultures treated with the ethanol extracts of C. nocturnum, A. scholaris [54], and the methanolic extracts of B. pilosa, O. trinervis, P. pentandrum [55]. These extracts exhibited strong inhibitory effects as noted by the measured zones of inhibition around the discs.

Table 2: Summary of QSI activities of the Ikalahan ethnobotanicals.

EthnobotanicalsChromobacterium ViolaceumPseudomonas aeruginosaStaphylococcus aureus



Disc diffusion assayPyocyanin productionSwarming motilityBiofilm formationDNaseα- HemolysinCoagulase








SolventEEMEEEMEHEXEEMEHEXMEEEMEHEXEEMEHEXEE
Bidens pilosa
Cestrum nocturnum
Sarcandra glabra
Oreocnide Trinervis
Pittosporum pentandrum
Lipang-daga
Derris elliptica
Alstonia scholaris
Ageratina adenophora
Ayapana triplinervis
: With QSI activity  : No QSI activity  : With antibacterial activity CE: Crude Extract CE-AuNPs: Biologically synthesized gold nanoparticles. QSI: Quorum sensing inhibition

2.2. Biofilm Formation

Biofilm formation is a QS-related process in which bacterial cells produce a complex matrix of extracellular polymeric substances that include polysaccharides and proteins that provide protection to the bacterial community and prevent or delay the penetration of antimicrobial agents into the cells [92-94]. Biofilms play a major role in the increased resistance of bacteria to antibiotics [95,96]. In fact, bacteria in biofilms tend to be more tolerant of antibiotics compared to those in the planktonic state [97]. Not only does it protect the bacterial community from antibiotics, but it also effectively blocks the host’s immune cells [98] and provides protection against sudden changes in the environment and mechanical damage [99,100].

Biofilm production presents a serious health concern as it is related to most persistent chronic infections [101] and contributes to clinical complications. Biofilms play a major role in the development of AMR and are the centers of genetic transfer of mobile elements [102]. Another factor to consider is that mutation and horizontal gene transfer (HGT) are more frequent in bacteria with biofilms. Biofilms provide ideal conditions for HGT through conjugation that enables the transfer of AMR genes [103]. Biofilm-forming bacteria often use this self-produced biofilm to attach to surfaces that cannot be immediately controlled by antibiotics [104]. Aside from the clinical settings, the incidence of biofilm is common in the environment. Biofilms are commonly associated with food contamination [105-108] and biofouling in water treatment membranes [96,109]. Many different bacteria and fungi, as well as other microbes, can produce biofilm. Approximately 80% of infectious diseases are related to biofilms [110]. Controlling the formation of biofilm is a significant step in controlling pathogenesis and antimicrobial resistance.

P. aeruginosa biofilms are the major cause of chronic infections that are persistent [111,112]. P. aeruginosa biofilms, as with other biofilm-forming bacteria, play a significant role in resisting antibiotics and the host immune system through several mechanisms [57,65]. It is therefore important to increase the susceptibility of P. aeruginosa to antimicrobials by controlling biofilm development and attachment or by destroying it [112] to attenuate bacterial virulence and pathogenicity, and consequently, antibiotic resistance. A number of Philippine ethnobotanicals showed antibiofilm activity against P. aeruginosa [Table 3]. Santos et al. [47] tested the different plant parts of Ilongot-E?ongot ethnobotanicals against a reference strain and one clinical isolate of P. aeruginosa. The crude extracts of A. intermedia, D. esculentum, E. indica leaves, H. suaveolens flowers, H. vulgaris, M. micrantha, and Talahib have biofilm inhibitory effects against P. aeruginosa clinical isolate. Against the reference strain P. aeruginosa PNCM 1335, a significant reduction in biofilm formation was observed in the crude extracts of A. intermedia, C. pentandra, E. indica, D. esculentum, H. suaveolens, H. vulgaris, M. micrantha, S. jamaicensis., U. lobata, and Talahib. These biofilm inhibition activities were confirmed through gene expression analyses of biofilm-linked genes (see discussion on the downregulation of QS-linked genes at the later part of the review). The Ikalahan methanolic crude extracts of C. nocturnum, P. pentandrum, and Lipang Daga (local name) also showed inhibition of biofilm formation in P. aeruginosa [43] [Table 2].

Table 3: Summary of QSI activities of the Philippine Ilongot-E?ongot ethnobotanicals.

EthnobotanicalsAeromonas hydrophilaStreptococcus agalactiaePseudomonas aeruginosa clinical isolatePseudomonas aeruginosa reference strainStaphylococcus aureus reference strainMRSACandida albicans








SolventBiofilm formationBiofilm formationBiofilm formationBiofilm formationCoagulaseCoagulaseDNaseBiofilm formation








CECE-AuNPsCECE-AuNPsCECE-AuNPsCECE-AuNPsCECECECECE-AuNPs
Hydrocotyle vulgaris
Mikania micrantha leaves
Dillenia philippinensis bark
Dillenia philippinensis leaves
Ceiba pentandra
Cymbopogon winterianus
Senna alata
Urena lobata
Premna odorata bark
Premna odorata leaves
Stachytarpeta jamaicensis leaves
Eleusine indica roots
Eleusine indica leaves
Diplazium esculentum
Phyllanthus urinaria
: With QSI activity  : No QSI activity  : With antibacterial activity CE: Crude Extract CE-AuNPs: Biologically synthesized gold nanoparticles. QSI: Quorum sensing inhibition

The Ilongot-E?ongot ethnobotanicals were also evaluated against aquaculture pathogens A. hydrophila and S. agalactiae biofilm formation. A significant decrease in A. hydrophila biofilm formation was observed using the crude extracts of 13 Ilongot-E?ongot ethnobotanicals namely C. pentandra, C. winterianus, bark and leaves of D. philippinensis, D. esculentum, roots and leaves of E. indica, H. vulgaris, M. micrantha, bark and leaves of P. odorata, P. urinaria, S. jamaicensis, and U. lobata [Table 3]. The plant extracts tested showed lower optical density (OD) values compared to the control (no extract) after performing the microtiter plate assay for biofilm formation, [33]. In S. agalactiae biofilm formation, fourteen (14) Ilongot-E?ongot ethnobotanical crude extracts, namely, C. pentandra, C. winterianus, C. alata leaves, bark and leaves of D. philippinensis, roots and leaves of E. indica, D. esculentum, M. micrantha, bark and leaves of P. odorata, P. urinaria, S. jamaicensis, and U. lobata [Table 3] showed a significant decrease in biofilm formation [53]. The genes related to biofilm formation were significantly downregulated as affected by the ethnobotanical extracts both in A. hydrophila and S. agalactiae (see later part of discussion).

The Ilongot-E?ongot ethnobotanicals were also tested in C. albicans biofilm formation [Table 3]. The OD values of the C. albicans clinical isolate culture treated with extracts of C. pentandra leaf, C. winterianus leaf, D. philippinensis leaf, D. esculentum, roots and leaves of E. indica, S. alata, H. vulgaris leaf, M. micrantha leaf, P. odorata bark, P. urinaria S. jamaicensis leaf, and U. lobata leaf showed significantly lower OD values ranging from 0.062 to 0.083 mg/mL compared to the negative control (no extract) with a higher value of 0.19 mg/mL [56] showing inhibition of biofilm formation and were confirmed through gene expression analyses (see discussion on inhibition of quorum-sensing-linked genes using Philippine ethnobotanicals - Section 4.0).

2.3. Coagulase Formation

S. aureus is the only known human disease-causing bacteria that produce coagulase [113]. Coagulase is a virulence factor involved in establishing host infections with S. aureus [114,115]. S. aureus is a significant human pathogen with a remarkable genetic competence for antibiotic resistance [116]. Through adaptive mutations, resistant strains such as methicillin resistant S. aureus and vancomycin-resistant S. aureus have reached epidemic proportions globally [116-118]. The slow development of effective antibiotics and rapidly evolving resistance make S. aureus infections challenging to manage [119]. Hence, new therapeutic modalities with less potential for resistance must be developed immediately [120,121]. The Philippine ethnobotanicals were evaluated against coagulase formation in S. aureus through the tube coagulase assay using rabbit plasma. The tube coagulase assay is performed to measure the production of coagulase enzyme by S. aureus and uses rabbit plasma. Coagulase is an enzyme that causes the plasma to clot by converting fibrinogen to fibrin [122]. Clotting reaction after 4–24 h of incubation indicates QS activity. Three ethnobotanical crude extracts of the Ilongot-E?ongot community showed inhibition of coagulation [37,50]. These are D. philippinensis bark, E. indica roots and S. jamaicensis leaves [Table 3]. Ethanol extracts of Ikalahan ethnobotanicals such as A. triplinervis, A. adenophora, D. elliptica, O. trinervis and S. glabra showed anti-coagulase activity against S. aureus [51] [Table 2].

2.4. α-Hemolysin

α-Hemolysin is a cytotoxic protein and a major QS-mediated virulence factor that plays a significant role in S. aureus pathogenesis [123-125]. S. aureus secretes hemolysins, one of which is the α-Hemolysin, which allows lysis of red blood cells. The α toxin is active against a wide range of mammalian cells and implicated in a wide range of S. aureus diseases such as skin and soft-tissue infections [126], pneumonia [125], bacteremia and sepsis [127], lethal peritonitis [128], septic arthritis, brain abscess and corneal infections [123].

The α-Hemolysin assay was done using Blood Agar supplemented with the ethnobotanical crude extracts. 24-h culture of S. aureus was streaked onto the agar and incubated for no more than 24 h. The absence of hemolysis in plates indicates inhibition of α-Hemolysin production by the ethnobotanical extracts. Only the ethanol and n-hexane extracts of Ikalahan ethnobotanicals A. scholaris, A. adenophora, A. triplinervis, B. pilosa, C. nocturnum, D. elliptica, O. trinervis, P. pentandrum, S. glabra, and Lipang Daga inhibited the production of α-toxin in S. aureus [Table 2] [48,49]. This was observed as the absence of hemolysis in the blood agar plates cultured with the bacteria compared to the negative control (water) where hemolysis was evident. Methanolic extracts of these ethnobotanicals failed to inhibit the production of α-Hemolysin.

2.5. Deoxyribonuclease (DNase)

S. aureus produces an enzyme that is capable of breaking down DNA [129]. DNase is a virulence factor [130] that allows S. aureus to evade immune cells, particularly the neutrophils, from attacking them. Neutrophils are a critical part of the innate immune system and the primary line of protection against invading pathogenic bacteria [131]. Some bacteria have the capacity to circumvent destruction by neutrophils [115]. In the case of S. aureus, this is made possible by the production of DNase [132]. Avoiding destruction, this allows the bacteria to invade tissues and cause infections [133,134]. DNase has also been linked to S. aureus-related pus-forming illnesses. Aside from this, DNase is known to contribute to virulence factor production such as maturation of biofilm and is further involved in bacterial growth [135,136]. In some countries, phenotypic coagulase tests are usually conducted to confirm infections by S. aureus [137].

Deoxyribonuclease (DNase) assay is done through the addition of hydrochloric acid (HCl). DNase production can be observed through clear zones of depolymerized DNA around the bacterial colonies. The bacterial cultures treated with methanolic extracts of D. elliptica and O. trinervis [52] and the ethanolic extracts of A. triplinervis, C. nocturnum, and O. trinervis [48] inhibited the phenotypic expression of DNase [Table 2]. Clear zones surrounding the bacterial streak and colonies suggest the presence of DNase [138,139], hence, the QSI activity was noted by the absence of clearing around the bacterial colonies that are opaque and whitish due to polymerized DNA.

2.6. Swarming Motility

Swarming is a QS-related process where coordinated movements allow bacteria to spread across a surface [140]. Since it is QS-linked, bacterial density and growth medium are critical for this process [141]. In P. aeruginosa, swarming aids the bacterial community to cause infections by producing secretions that reduce surface tension in their environment [141,142]; it is a necessary step for bacterial migration and colonization as well as a major contributor for the production of biofilms. In the reviewed papers, only the Ikalahan ethnobotanical methanolic extracts (A. adenophora, A. triplinervis, A. scholaris, B. pilosa, C. nocturnum, D. elliptica, O. trinervis, P. pentandrum, S. glabra, and Lipang daga) significantly controlled swarming motility in P. aeruginosa [42] [Table 2].

2.7. Pyocyanin Production

Pyocyanin is a P. aeruginosa virulence factor that contributes to its pathogenesis by invasion and inhibition of several cells and cellular processes in humans such as those in respiratory epithelial cells and immune cells [143,144]. Only the ethanolic extracts of Ikalahan ethnobotanicals O. trinervis, C. nocturnum, and A. triplinervis showed significant inhibition of pyocyanin production in P. aeruginosa [44] [Table 2]. A number of Ikalahan ethnobotanical methanol extracts showed lower pyocyanin production (B. pilosa, O. trinervis, A. triplinervis and D. elliptica) [42] but were not significantly different from the negative control.


3. BIOLOGICALLY SYNTHESIZED GOLD NANOPARTICLES USING THE PHILIPPINE ETHNOBOTANICALS

Nanotechnology had gradually pushed drug design into new heights through novel approaches. Among the potential applications of nanotech-designed materials is the synthesis of nanoparticles to target multidrug resistance in bacteria. As mentioned earlier, MDR has become a global health concern. To address this, nanoparticles offer advantages in designing antimicrobial drugs through extremely reduced size, biocompatibility, and targeted drug delivery [145-147]. Among nanotechnology approaches, green synthesis of nanoparticles draws interest as it offers solutions to control diseases without the toxicity commonly associated with nanoparticles synthesized using the standard physical and chemical methods. Toxicity is avoided in nanoparticle green synthesis as it utilizes natural products as capping or reducing agents. The method also reduces the use of toxic chemicals, requires less energy, is cost-effective, relatively fast and easy to perform, and generally with less pollution, and thus, environment-friendly [148,149]. The exceptional properties of natural metabolites are tapped for the stable synthesis of nanoparticles [149]. While the research in biosynthesized nanoparticles is mostly still in the laboratory phase and their sustainability has to be established, these NPs show considerable potential applications in biomedical science and other industries [150].

Among the metallic nanoparticles, gold nanoparticles (AuNPs) have gained significant attention in drug development due to their unique properties. AuNPs are generally considered biocompatible, making them suitable for use in biological systems, particularly for applications in drug delivery [151]. It is an ideal carrier of antimicrobial agents as this is the least toxic metal [152] and does not cause adverse reaction with human body tissues and fluids. AuNPs are also relatively stable in the body due to its high reduction potential [153]. Moreover, the tunability of AuNPs allow for precise control of size and shape to cater to targeted drug delivery while minimizing side effects applications [154,155]. This property is crucial as their extremely reduced size allow them to penetrate cells easily and their surface can be modified to attach therapeutic agents. Furthermore, the Enhanced Permeability and Retention (EPR) of AuNPs allows them to accumulate in diseased tissues such as cancer tumors for extended period of time compared to normal tissues [156,157].

Combining the potential of nanoparticles for effective drug delivery in disrupting QS with the antimicrobial power of natural metabolites is a novel strategy to address multidrug resistance in microbes. On this premise, the Ilongot-E?ongot ethnobotanicals were utilized to synthesize gold nanoparticles which were consequently evaluated for anti-QS activities. The formation of the gold nanoparticles using the ethnobotanicals was confirmed through SPR peaks observed in ultraviolet-visible spectroscopy and the observation of the change in color to pink-red indicates a reduction in size. These were tested against P. aeruginosa reference strain and clinical isolate [33], A. hydrophila [33], S. agalactiae [53], and C. albicans [56] biofilm formation [Table 3]. The evaluated ethnobotanically synthesized NPs displayed efficiency in inhibiting biofilm formation in the test bacteria whereas treatments with biosynthesized NPs showed significantly lower biofilm formation compared to treatments with only crude extracts. Table 3 shows the comparison of the biosynthesized NPs (CE-AuNPs) with crude extracts (CEs). NPs synthesized using C. pentandra, C. winterianus, D. philippinensis bark, E. indica roots, H. vulgaris, M. micrantha, P. urinaria, P. odorata, and S. alata had displayed antibacterial activity in the pre-screening for QS assays showing a high level of action against A. hydrophila [33]. To continue to subsequent QS assays, the sub-MIC (minimum inhibitory concentration) has to be determined, of which these were not included in the reviewed studies. The same case can be observed for most biosynthesized NPs included in the evaluation against S. agalactiae [53]. A number of biosynthesized gold nanoparticles were also shown to be more efficient than crude extracts in inhibiting biofilm formation in both clinical isolates and reference strains of P. aeruginosa. In cases where both CE and CE-AuNPs displayed biofilm formation inhibition, several AuNP treatments had significantly higher biofilm formation inhibition as was the observation in A. hydrophila, S. agalactiae, and C. albicans [33,53,56].

Current control strategies for MDR in bacteria only include chemical-based drugs and antiseptic solutions [102] with reduced penetration in the cell or limited access because of biofilms. Nanoparticles constitute a novel option as antimicrobial drugs can be delivered more efficiently through their extremely reduced nanosize and increased surface area that consequently results in faster penetration of the cell membrane and other biological barriers. Integrated with active metabolites, its applications in the medical field is wide.


4. INHIBITION OF QUORUM-SENSING-LINKED GENES USING PHILIPPINE ETHNOBOTANICALS

QS is made possible by collective gene expression brought about by the secretion of signal molecules that are triggered once the density has reached a certain threshold. It is a complex signaling circuit with several linked pathways [8]. The LuxI/LuxR circuit regulates QS in gram negative bacteria. In P. aeruginosa, two major circuits that are homologues of LuxI/LuxR regulate QS: LasI/LasR and RhlI/RhlR. Both homologues, as is in LuxI/LuxR, produce homoserine lactones (HSL) as autoinducers. When HSLs reach a certain threshold level, their complex with LasR/RhlR activates the transcription of genes that leads to the expression of virulence factors [158]. The Las and Rhl systems, in conjunction with the respective HSLs, regulate up to 353 genes, accounting for approximately 6% of the P. aeruginosa genome [159]. When the threshold quorum concentration is reached, the QS molecules C4-HSL and 3-oxo-C12-HSL, which are synthesized by LasI and RhlI, respectively, are recognized by their associated receptors, LasR and RhlR. A cascade of gene expression of virulence genes follows after the activation of LasR, a regulator of pathogenicity in P. aeruginosa [160-162]. Subsequently, if lasR expression is blocked, regulation of other QS-linked genes, particularly those that play a role in biofilm formation, will be affected [163].

In Gram-positive bacteria, the signal molecule is in the form of peptides produced from precursors called autoinducing peptides (AIPs) [11]. Common to other QS systems, once the AIPs reaches a threshold concentration, a cascade of expression for the production of several virulence factors follow [121,164]. In S. aureus, the accessory gene regulator (agr) system produces this signal molecule and plays a significant role in the production of S. aureus virulence and pathogenesis [165]. The production extracellular toxins and enzymes by the agr system [121,166,167] is critical for S. aureus colonization and resistance to host immune response [168].

In P. aeruginosa, QS-linked genes were significantly downregulated in treatments in several Ilongot-E?ongot ethnobotanical extracts as well as in biosynthesized gold nanoparticles [Table 3]. The significant decrease in biofilm formation by plants extracts and biosynthesized nanoparticles using M. micrantha, A. intermedia, and Talahib was confirmed through the downregulation of lasR [47] and also rhlR [46] validating the results in QSI biofilm quantification. Since lasR is a transcription regulator of several QS virulence factors e.g. biofilms, its downregulation may mean that the molecules in the ethnobotanical extracts could have blocked its transcription or a genetic pathway, leading to it that led to the decrease in biofilm production.

AhyR expression also showed downregulation in A. hydrophila as affected by the crude ethnobotanical extracts and the biosynthesized AuNPs [33] [Table 3]. AhyR is a luxR homologue in A. hydrophila responsible for HSL production and regulates pathogenicity [169,170]. As in other bacteria, blocking AhyR expression likewise results in the control of the QS cascade affecting the production of other virulence factors.

In C. albicans, the molecular expression of two biofilm-linked genes, Bcr1 and Hsp90, showed significant downregulation as affected by both ethnobotanical crude extracts and the biosynthesized AuNPs [56] [Table 3]. Specifically, Bcr1 expression was significantly downregulated in the treatments with decreased biofilm formation such as in H. vulgaris, M. micrantha leaf, C. pentandra leaf, C. winterianus leaf, S. alata, U. lobata leaf, D. philippinensis leaf, P. odorata bark, S. jamaicensis leaf, E. indica roots, D. esculentum, E. indica leaf, and P. urinaria leaf as compared to treatments without ethnobotanical extracts used. Bcr1 is a transcription regulator. The polysaccharide matrix in C. albicans is regulated by the expression of Bcr1. The intricate biofilm and its complex polysaccharide matrix are therefore affected by Bcr1 downregulation [171], which suggests that biofilm production will be suppressed or will not result in a robust extracellular matrix. C. albicans culture treated with CEs of H. vulgaris, M. micrantha leaf, C. pentandra leaf, C. winterianus leaf, S. alata, U. lobata leaf, D. philippinensis leaf, P. odorata bark, S. jamaicensis leaf, E. indica roots, D. esculentum, E. indica leaf, and P. urinaria showed significant downregulation of Hsp90. As a key regulator of biofilm development and drug resistance in C. albicans [172], compromised Hsp90 regulation leads to weak biofilm formation [173]. Hence, targeting Hsp90 can be tapped for C. albicans therapy and drug resistance.

Ilongot-E?ongot ethnobotanicals S. jamaicensis leaves. E. indica roots and D. philippinensis bark significantly downregulated agrA confirming the inhibition of coagulase formation. A number of these ethnobotanicals also displayed downregulation of agrA in S. agalactiae [53].


5. FUTURE PERSPECTIVES

The papers included in this review have proven that Philippine ethnobotanicals possess QSI actions in virulence factors in bacteria such as violacein formation [54,55], a- Hemolysin [44,45], swarming motility [42], DNase [48], pyocyanin production [42,44], coagulase [50,51], and biofilm formation [33,43,46,47,53,56], showing the immense prospects of tapping these plants for anti-virulence drug design. Aside from QSI activities, these plants have shown potent biological activities against gout [174], cancer cell lines [175], diabetes [176,177], inflammation and pain [178], and also possesses antioxidant properties [179]. These results present opportunities for further evaluations to exploit the potential of Philippine ethnobotanicals. All these plants have been used for centuries in traditional folk medicine to treat infections and diseases that are being practiced today.

Not much research on QSI activities has been reported on Philippine ethnobotanicals. Research targeting bacterial QS using ethnobotanicals is largely unexplored at present; hence, this offers an additional area of research on plants with pharmacological potential leading toward drug development. The Philippine ethnobotanicals showed considerable potential as sources of QS inhibitory compounds for new therapeutic directions in preventing pathogenicity without the threat of the development of bacterial resistance, hence, determining these molecules offer a new direction on this research. In addition, while laboratory-based assays indicate the huge promise of QSI agents, in vivo research on animal models needs to be conducted to substantiate in vitro results.


6. CONCLUSIONS

Ethnobotanicals have not been fully tapped for applications on QS-based drug development. The applications of ethnobotanicals and QS inhibition are timely and provide a wide range of long-term solutions to human and animal health. All Philippine ethnobotanicals from the two ethnic communities included in this review showed inhibition on one or more virulence factors highlighting their activities against QS and emphasizes their potential for QS-based drug development.

QS inhibition is a practical option in controlling pathogenesis that avoids antibiotic resistance. QS inhibition only targets the production of virulence, without affecting bacterial growth. This limits the exposure of bacteria to selective pressure and the evolution of resistant mutants, hence, seen to be a practical alternative to antibiotic management. In recent years, intensive research on QS mechanisms has presented the potential to control resistance. Integrating the bioactive molecules from ethnobotanicals with inhibiting QS provides a novel solution to microbial multidrug resistance. With the World Health Organization’s announcement in 2014 of the beginning of the post-antibiotic era, interest is now geared toward exploring new therapies that target the production of virulence factors instead of directly killing bacteria.

Although much research has been explored in targeting QS as a strategy to control bacterial pathogenesis, still, several issues have to be resolved to fully harness the potential of QSI as a novel approach in the fight against microbial infection and resistance. These limitations include evaluations on its efficacy in vivo, interactions with the host physiology, reactions with other compounds and long-term effectiveness. As with the majority of antibiotics, targeting QS may also impact not only pathogenic bacteria but also beneficial microbes. Also, the high specificity and complexity of QS systems makes it challenging to develop a broad-spectrum antimicrobial drug that can serve as universal QS inhibitor which can target multiple pathogens. Resolving these challenges is critical for the advancement of QS-based drugs. Albeit, the field of QS-based drug development is dynamic, and constantly delving on the mechanisms involved to optimize the potential applications and overcome limitations and challenges.


7. AUTHORS’ CONTRIBUTIONS

All authors made substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data; took part in drafting the article or revising it critically for important intellectual content; agreed to submit to the current journal; gave final approval of the version to be published; and agreed to be accountable for all aspects of the work. All the authors are eligible to be an author as per the International Committee of Medical Journal Editors (ICMJE) requirements/guidelines.


8. FUNDING

This article received no funding from any institutions or agencies.


9. CONFLICTS OF INTEREST

The authors report no financial or any other conflicts of interest in this work.


10. ETHICAL APPROVALS

This study does not involve experiments on animals or human subjects.


11. DATA AVAILABILITY

All data analyzed in this article are available from the author on reasonable request.


12. USE OF ARTIFICIAL INTELLIGENCE (AI)-ASSISTED TECHNOLOGY

The authors declares that they have not used artificial intelligence (AI)-tools for writing and editing of the manuscript, and no images were manipulated using AI.


13. PUBLISHER’S NOTE

All claims expressed in this article are solely those of the authors and do not necessarily represent those of the publisher, the editors and the reviewers. This journal remains neutral with regard to jurisdictional claims in published institutional affiliation.


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