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Microbiology and Biotechnology Letters

Research Article(보문)

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Fermentation Microbiology  |  Applied Microbiology

Microbiol. Biotechnol. Lett. 2023; 51(4): 432-440

https://doi.org/10.48022/mbl.2307.07012

Received: July 25, 2023; Revised: October 14, 2023; Accepted: November 1, 2023

Antibiotic Reversal Activity of Piper longum Fruit Extracts against Staphylococcus aureus Multi-Drug Resistant Phenotype

Maryam Salah Ud Din1, Umar Farooq Gohar1, Hamid Mukhtar1, Ibrar Khan2, John Morris3, Soisuda Pornpukdeewattana4*, and Salvatore Massa4,5*

1Institute of Industrial Biotechnology, Government College University, Lahore, Pakistan
2Department of Microbiology, Abbottabad University of Science and Technology, Abbottabad, Pakistan
3School of Industrial Education and Technology, King Mongkut's Institute of Technology Ladkrabang, Bangkok, Thailand
4Faculty of Food Industry, King Mongkut’s Institute of Technology Ladkrabang, Bangkok, Thailand
5Department of Agriculture, Food, Natural Resource and Engineering, University of Foggia, Foggia, Italy

Correspondence to :
S. Pornpukdeewattana soisuda.po@kmitl.ac.th
S. Massa salvatore.massa@unifg.it

Abstract

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Irrational and injudicious use of antibiotics, easy availability of them as over-the-counter drugs in economically developing countries, and unavailability of regulatory policies governing antimicrobial use in agriculture, animals, and humans, has led to the development of multi-drug resistance (MDR) bacteria. The use of medicinal plants can be considered as an alternative, with a consequent impact on microbial resistance. We tested extracts of Piper longum fruits as new natural products as agents for reversing the resistance to antibiotics. Six crude extracts of P. longum fruits were utilized against a clinical isolate of multidrug-resistant Staphylococcus aureus.The antibiotic susceptibility testing disc method was used in the antibiotic resistance reversal analysis. Apart from cefoxitin and erythromycin, all other antibiotics used (lincosamides [clindamycin], quinolones [levofloxacin and ciprofloxacin], and aminoglycosides [amikacin and gentamicin]) were enhanced by P. longum extracts. The extracts that showed the greatest synergy with the antibiotics were EAPL (ethyl acetate [extract of] P. longum), n-BPL (n-butanol [extract of] P. longum), and MPL (methanolic [extract of] P. longum The results of this study suggest that P. longum extracts have the ability to increase the effectiveness of different classes of antibiotics and reverse their resistance. However, future studies are needed to elucidate the molecular mechanisms behind the synergy between antibiotic and phytocompound(s) and identify the active biomolecules of P. longum responsible for the synergy in S. aureus.

Keywords: Piper longum, antibiotic resistance reversal, antibiotics, plant extracts

Graphical Abstract


Introduction

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The circulation of microorganisms resistant to antimicrobials and the worldwide spread of antibiotic resistance genes represents one of the biggest risks to mankind in the twenty first century [1, 2]. The rise of multi-drug-resistant bacteria is considered a major threat to the health of humanity by both the World Health Organization [3] and World Economic Forum [4]. Globally, although difficult to calculate, it is estimated that 700 000 deaths each year are attributed to antimicrobial resistance (AMR) and have an economic impact of $100 trillion by 2050 [5].

Resistance against antibiotics can be acquired due to alternations in genetic material that may lead to a chemical alteration in a target protein with a decreased affinity for the antibiotic. More often, antibiotic resistance is due to the transmission of R plasmids, or other mobile genetic elements, such as transposons and phage DNA, carrying genes encoding the inactivation or degradation of the antibiotic or its extrusion by active efflux pumps [2].

The emergence of multidrug-resistant diseases is due to the inappropriate and often unjustified use of antibiotics [2]. Easy access to non-prescription drugs in developing countries and the absence of legislative policies covering the use of antimicrobials in humans, farm animals, agriculture and fish farming led to the development of MDR pathogens that are associated with various disease outbreaks [6, 7]. As a result of these multidrug-resistant pathogens, the number of available antibiotics decreased for their treatment and hospital care became more expensive and took longer time [8]. The situation is especially alarming because very few new antibiotics have been discovered recently [9]. Paradoxically, as bacterial resistance to antibiotics increases, the number of pharmaceutical companies producing new antimicrobial agents decreases. The reasons for this phenomenon are various, including the fact that pharmaceutical companies find it more profitable to invest in the research of drugs aimed at treating chronic diseases, but above all because strains resistant to the new drug appear shortly after the introduction of a new antibiotic on the market [10]. Therefore, there is a continuing quest for unconventional sources of active drugs. Herbal medicines have been widely accepted, as plants are known to produce substances of chemotherapeutic value [11]. Over time, plants have developed particular mechanisms with the aim of protecting themselves from different microorganisms (bacteria, viruses and fungi) through the production of secondary metabolites (or bioactive phytochemicals) present in leaves, flowers, seeds, roots, stems and fruits [10]. The most important secondary metabolites are alkaloids, flavonoids, organosulfur, phenolic compounds, and tannins that have strong activity against microbial infection [12]. Small molecular weight (MW) phytochemicals (usually less than 500 MW) have shown synergy with antibiotics already available [13]. Herbal medicines and their secondary metabolites have been found to target almost all antibiotic resistance mechanisms. For example, epigallocatechin gallate (EGCG, the major ingredient of tea catechins) inhibits the enzymatic degradation of antibiotics by blocking β-lactamases [14]; carnosic acid (isolated from Rosmarinus officinalis) inhibits bacterial efflux pumps [15] and corilagin from Arctostaphylos uva-ursi inhibits penicillinbinding proteins (PBP) 2a, a modified receptor [16].

Pippali or long pepper is the common name of Piper longum Linn (in the Piperaceae family) and it is harvested in the tropical and subtropical regions of Asia and the Pacific islands [17, 18]. P. longum has various medicinal properties due to secondary metabolites and is used in traditional medicine to treat conditions such as colds, headaches, fever, flu, coughs, skin infections, leprosy, hemorrhoids, pneumonia and stomach pain [19]. Its different parts contain bioactive compounds such as piperamides, flavonoids, lignans, and essential oils [20]. The piperine (PIP) alkaloid, the main constituent of P. longum (long pepper) and P. nigrum (black pepper), is the most significant bioactive compound from a pharmacological point of view. According to some reports, PIP combined with antimicerobials showed efflux-blocking activity as a key mechanism against Staphylococcus aureus [21, 22] and Mycobacterium tuberculosis [23, 24]. These studies suggest that PIP is an efflux pump inhibitor (EPI) and may increase the effectiveness of ‘old’ antibiotics (for example, ciprofloxacin against S. aureus or against M. tuberculosis). In addition, aqueous and methanolic extracts of P. longum can reverse antibiotic resistance by curing R-plasmid (i.e. eliminating resistant plasmids) in multiple-drug-resistant bacterial strains [25]. Considering the important bioactivities of P. longum and the use of its crude extracts in folk medicine, we investigated its antibacterial property. In particular, the preliminary aim of the current study was to search for the antibiotic reversal resistance of various solvent extracts of P. longum against a selected MDR, S. aureus strain of clinical origin.

Material and Methods

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Plant material

Mature seeds of P. longum were obtained from the local market of Lahore, Pakistan. The taxonomic identity was confirmed with the assistance of Dr. Zaheer-ud-din Khan (Distinguished Professor) at the Department of Botany, Government College University (GCU) Lahore, Pakistan. A plant, with voucher number P. longum “GCU.Herb.Bot.3563”, was stored in the Department of Botany Department Herbarium, GCU, for future uses.

Cleaning of plant material

The material of the plant (i.e. the fruit of the plant) was washed three times with water and dried at 40℃ in an oven for two days. After drying, the material was ground into a fine powder, which was passed through a 1.17 mm sieve.

Extract preparation

The liquid-liquid extraction method was used to obtain extracts of plant material according to Mushtaq et al. [25]. From P. longum, six extracts were obtained and labeled by the solvent used: aqueous (APL), methanolic (MPL), n-hexane (n-HPL), chloroform (CPL), ethyl acetate (EAPL), and n-butanol (n-BPL) P. longum extracts. The extraction fractionation scheme is shown in Fig. 1. The plant extracts were kept at 4℃ until the next use.

Figure 1.The schematic method used to prepare plant extracts in the different solvents (from Din et al. 2022. Appl. Sci. 12: 12542. https://doi.org/10.3390/app122412542)

Bacterial strains

S. aureus, bacterial strain LH344, was obtained from the Department of Microbiology, (Culture Collection) Jinnah Hospital, Lahore, Pakistan, and was validated by standard biochemical tests [26]. S. aureus (ATCC 25923) was used as control of media testing and the CLSI disk diffusion method (see below). The strains were kept at 4℃ on Mannitol Salt Agar (MSA) and subcultured before each test for 24 h on Mueller Hinton Agar (MHA).

Antibiotic susceptibility test (AST)

AST of S. aureus, bacterial strains LH344, was done on MHA plates using the Kirby-Bauer disc diffusion method following CLSI [27] guidelines. In brief, wellisolated colonies were suspended in 0.85% saline and diluted in 1:10 to match the turbidity according to 0.5 McFarland standards (a density of 1 × 108 CFU/ml). In a bacterial suspension, a cotton swab was dipped and streaked on the MHA plates for lawning. When the plates were dried the antibiotic disc was placed on the agar with the help of forceps and gently pressed. Plates were incubated at 37℃ for 24 h. The following antibiotics were used (μg/disc): cefoxitin (30); erythromycin (15); clindamycin (10); levofloxacin (5); ciprofloxacin (5); amikacin (30) and gentamicin (10). The zone of inhibition was measured after 24 h. The diameters around the discs were measured and interpreted according to CLSI guidelines as sensitive, intermediate, or resistant [27].

Antibiotic resistance reversal activity

The different plant extracts were used to check the ability of P. longum to reverse antibiotic resistance. MHA was prepared in a flask. In MHA petri plates 1 ml of plant extracts was added during the pouring step. Then, after agar solidification, a colony of S. aureus was aseptically removed from MSA and emulsified in the sterile 0.85% saline solution. The bacterial suspension turbidity was matched with the McFarland standard. A sterile cotton swab was used and streaked on the MHA plate. When the plates were dried, the antimicrobial discs were placed on the agar plate. Plates were then incubated for 24 h at 37℃. To measure the zone of inhibition of each antibiotic a metric ruler was used. The test organism zone of inhibition was compared with the CLSI [27] table. The difference between before and after the antibiotic resistance reversal procedure was compared. All experiments were run in triplicate. Similar experiments were conducted using solvents alone to ascertain whether they had an inhibitory effect on the bacterial growth zone.

Results and Discussion

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Antibiotic susceptibility test (AST) of S. aureus

Antibiotic susceptibility test (AST) results of S. aureus are reported in Table 1. The inhibition zone diameters were: cefoxitin 12 mm, erythromycin 11 mm, clindamycin 10 mm, levofloxacin 12 mm, ciprofloxacin 11 mm, amikacin 14 mm, and gentamicin 14 mm. The area of inhibition of the test organism was compared with the CLSI [27]. Table 1 indicates that if the zone of inhibition is equal to or less than 20, 13, 14, 15, 15, 12, and 12 mm, respectively, the bacterium in question is resistant to the antibiotic tested. S. aureus was resistant to all antibiotics except amikacin and gentamicin, for which drugs the pathogen showed intermediate sensitivity (Table 1).

Table 1 . Antibiotic susceptibility of Staphylococcus aureus strain LH344.

Zone of inhibition for test strain (mm)Zone of inhibition according to CLSIa (mm)
SensitiveIntermediateResistant
Cefoxitin (30 μg)12≥25-≤20
Erythromycin (15 μg)11≥2314-22≤13
Clindamycin (10 μg)10≥2115-20≤14
Levofloxacin (5 μg)12≥1916-18≤15
Ciprofloxacin (5 μg)11≥2116-20≤15
Amikacin (30 μg)14≥1713-14≤12
Gentamicin (10 μg)14≥1513-14≤12

a CLSI, Clinical and Laboratory Standards Institute [27]

Antibiotic resistance reversal activity

For checking antibiotic resistance reversal activity, P. longum extracts were mixed with MHA (Mueller Hinton Agar). An antibiotic susceptibility test (AST) was performed on the lawn growth of the S. aureus test strain. Then plant extract AST results were compared with original antibiotic susceptibility test results. The results are presented in Figs. 2-8. Zones of inhibition did not increase using solvents alone and therefore these results are not shown.

Figure 2.Zone of inhibition (mm) of antibiotic cefoxitin result compared with plant extracts of Piper longum treated zones in Staphylococcus aureus. The labels indicate the solvent used: MPL=methanol; n-HPL=n-hexane; CPL=chloroform; n-BPL=butanol; EAPL=ethyl acetate; APL=water. Values are means of three parallel replicates. Error bars indicate the standard error from the mean.

Figure 3.Zone of inhibition (mm) for erythromycin compared with Piper longum extract treated zones in Staphylococcus aureus. See Fig. 1 for abbreviations.

Figure 4.Zone of inhibition (mm) of antibiotic Clindamycin result compared with plant extract of Piper longum treated zones in Staphylococcus aureus. See Fig. 1 for abbreviations.

Figure 5.Zone of inhibition (mm) for Levofloxacin compared with Piper longum extract treated zones in Staphylococcus aureus. See Fig. 1 for abbreviations.

Figure 6.Zone of inhibition (mm) of ciprofloxacin compared with extracts of Piper longum treated zones in Staphylococcus aureus. See Fig. 1 for abbreviations.

Figure 7.Zone of inhibition (mm) of amikacin compared with extracts of Piper longum treated zones in Staphylococcus aureus. See Fig. 1 for abbreviations.

Figure 8.Zone of inhibition (mm) of gentamycin compared with P. longum extract treated zones in S. aureus. See Fig. 1 for abbreviations.

Cefoxitin. The zone of inhibition of cefoxitin was 12 mm before being treated with plant extracts (Fig. 2). With MPL extract of P. longum, the zone of inhibition of cefoxitin increased to 18 mm. With the n-hexane, nbutanol, chloroform, ethyl acetate, and aqueous extracts, the zone of inhibition increased only 1−2 mm, compared to the zone of inhibition of cefoxitin before being treated with plant extracts. Since the sensitivity zone of cefoxitin is equal to or greater than 25 mm (Table 1), our results showed no synergy between the P. longum extracts and cefoxitin. Cefoxitin is a beta-lactam antibiotic belonging to the cephalosporin family that works by interfering with the cell wall synthesis (peptidoglycan) of growing bacteria [28]. Although the present study showed no synergy between secondary metabolites of P. longum and the beta-lactam antibiotic (cefoxitin), synergy with other herbal extracts has been seen in other studies, for example, epigallocatechin gallate (the main constituent [60%] of tea catechins) and ampicillin (a beta-lactam antibiotic), which is directly bound to the peptidoglycan through the bacterial cell wall and interfere with its integrity and biosynthesis [29]. The current study suggested that P. longum extract had no, or very little, effect on cell wall inhibition.

Erythromycin. The zone of inhibition of erythromycin was 11 mm before being treated with plant extracts (Table 1). Using P. longum extracts, the area of inhibition increased maximum to a 21 mm with EAPL extract, which had little significance because the value falls in the intermediate zone and the sensitive zone was greater than or equal to 23 mm (Table 1). The MPL extract enhance the zone of inhibition by 20 mm and was smaller for n-BPL (17 mm), n-HPL, and CPL (16 mm). APL did not change the inhibition zone for erythromycin (Fig. 3). Erythromycin belongs to the macrolides class of antibiotics, which inhibit bacterial growth by inhibiting protein synthesis [30]. Ahirrao et al. [31] reported the isolation of phytoconstituents from the methanolic extract of the Piper cubeba fruit (a plant in the Piperaceae family) and investigated their effect against the MsrA efflux pump of the S. aureus RN4220 resistant to macrolides. They found that four phytoconstituents compounds (pellitorine, tetrahydropiperine, sesamin and piperic acid) when combined with the antibiotic erythromycin in S. aureus RN4220, showed a 2−8 fold decrease in the minimum inhibitory concentration (MIC) of erythromycin [31]. In our study, no synergy was observed between erythromycin and the P. longum extracts.

Clindamycin. The zone of inhibition of clindamycin was 10 mm before being treated with plant extract, while the sensitive zone was equal to or greater than 21 mm (Table 1). By utilizing plant extracts of the P. longum, the zone of inhibition enhanced up to 31mm with EAPL extract (Fig. 4). The MPL of P. longum and n-HPL enhanced the zone of inhibition to 29 and 26 mm, respectively. CPL, n-BPL, and APL enhanced the inhibition zone to 24 mm (Fig. 4). Clindamycin belongs to the lincosamide group of antibiotics, which inhibit the growth of bacteria by blocking the protein synthesis mechanism [30]. Clindamycin is considered as the last therapeutic chance which target multi-resistant S. aureus strains. Iobbi et al. [32] reported that sclareol, a labdane diterpene, showed synergistic activity with the clindamycin against (MRSA) methicillin-resistant S. aureus with an FIC (fractional inhibitory concentration) value of 0.4. Labdanum-type diterpenoids are present in the tissues of fungi, insects, and marine organisms and in essential oils, resins, and tissues of higher plants. In addition, Iobbi et al. [32] have reported antimicrobial activity of diterpenoids against multi-drug resistant (MDR) strains. In the present research, all the extracts (but especially EAPL and MPL extracts) showed good antibiotic resistance reversal activity, as the sensitive zone inhibition of clindamycin was ≥21 (Table 1).

Levofloxacin. The area of inhibition of levofloxacin was 12 mm before being treated with P. longum extracts (Fig. 5), while the sensitive zone was equal to or greater than 19 mm (Table 1). After extracting with n-HPL and EAPL, the area of inhibition enhanced to 19 mm (Fig. 5). With MPL extract, the area of inhibition enhanced to 18 mm, whereas other solvents increased the zone by only 1 (n-BPL) or 2 mm (CPL). The APL, n-HPL and EAPL extracts enhanced the activity of levofloxacin, indicating a promising use in the treatment of disease caused by S. aureus bacterial strains which are resistant to it. Levofloxacin (as ciprofloxacin, norfloxacin, and others) belongs to the fluoroquinolones antibiotic class that has a selective and bactericidal effect by interfering with bacterial DNA replication. Leal et al. [33] investigating the potential antimicrobial activity of the essential oil from the plant Piper caldense (EOPC), found that EOPC decreased the norfloxacin minimum inhibiting concentration (MIC) values against S. aureus bacterial strains overproducing efflux pumps (NorA, MepA and QacC pumps). This indicated that EOPC was a main source of phytochemicals acting agents such as NorA, MepA, and QacC inhibitors [33]. Our results were consistent with Leal et al. [33].

Ciprofloxacin. The zone of inhibition of ciprofloxacin was 11 mm before being treated with plant extracts (Fig. 6), whereas the sensitive zone was equal to or greater than 21 mm (Table 1). Figure 6 shows the inhibition zone increased up to 22 mm with both n-HPL and EAPL, thus showing synergy with ciprofloxacin. The zone of inhibition increased by only 1 mm with n-BPL and APL, remained unchanged with the MPL extract, and only 2 mm with CPL. Ciprofloxacin (a fluoroquinolone antibiotic) is a very common and widely used antibacterial agent [34]; it is typically less effective against the grampositive cocci (including S. aureus, S. pneumoniae, and Enterococcus faecalis) than gram-negative rods [35]. The presence of efflux pumps in gram-positive bacteria plays an important role in contributing to antibiotic resistance by actively extruding fluoroquinolones [36, 37]. Indeed, Khan et al. [21] found that piperine, the major plant alkaloid present in P. longum, in combination with ciprofloxacin, markedly reduced the MICs for S. aureus; they demonstrated that piperine enhancement occurred by the inhibition of ciprofloxacin efflux from the S. aureus [21].

Amikacin. The area of inhibition of the amikacin was 14 mm before being treated with the plant extracts (Fig. 7), but the sensitive zone was 17 mm or greater (Table 1). With P. longum extracts, the area of inhibition enhanced up to 21 mm with EAPL extract, which was important, because the value falls in the sensitive zone as shown in Table 1. With APL and n-HPL extracts, the zone of inhibition increased up to 19 mm, with CPL it increased to 17 mm, whereas with methanol and n-BPL extracts, the zone of inhibition increased only 1 to 2 mm. Amikacin belongs to the antibiotic class named aminoglycosides: these bactericidal agents inhibit bacterial protein synthesis by binding irreversibly to the bacterial 30S ribosomal subunit [28]. Our results are similar to those reported by Macedo da Silva et al. [38], who found an antibiotic-modulatory activity between aminoglycosides amikacin and essential oils from Piper mosenii C. DC against S. aureus.

Gentamicin. The zone of inhibition of gentamycin was 14 mm before being treated with plant extracts (Fig. 8). The sensitive zone was 15 mm or greater (Table 1), but by using the ethyl acetate extract, the zone of inhibition increased up to 22 mm, whereas it increased to 16−18 mm with methanolic (MPL), chloroform (CPL) and n-butanol (n-BPL) extracts. Therefore, a marked synergy was found between gentamicin and the aforementioned P. longum extracts (EAPL, MP, CPL, and n-BPL). With n-HPL and APL extracts, the zone of inhibition enhanced only 1 to 2 mm. Gentamicin has the same mechanisms of action as amikacin, as it belongs to the same class of aminoglycoside antibiotics [28]. Similar outcomes were obtained by Macedo da Silva et al. [38], who demonstrated that the essential oils of the Piper mosenii C. DC (α-pinene and bicyclogermacrene) showed synergy of amikacin and gentamicin against the multi-resistant strain of both E. coli and S. aureus.

In conclusion, research on the plant-based drugs has increased significantly with the hope that some medicinal plants can be used to treat bacterial infections from antibiotic-resistant bacteria. The effectiveness of antimicrobials of plant origin largely depends on the presence of wide range of secondary metabolites and their extraction methods. In this study, apart from cefoxitin and erythromycin, the other antibiotics tested (clindamycin, quinolones, and aminoglycosides) were enhanced by P. longum crude extracts. The solvents that led to the strongest synergy with the antibiotics were ethyl acetate, n-butane and methanol. We speculate that P. longum extracts can reverse antibiotic resistance in S. aureus and increase the effectiveness of current drugs by inhibiting efflux pumps or eliminating plasmids responsible for antibiotic resistance. Indeed P. nigrum contains alkaloids (piperine and piperlongumine), flavonoids, glycosides, and tannins that have resistance reversal activity [21, 22, 25, 31]. However, further elaborate phytochemical analyses are needed to identify the main P. longum compounds responsible for the activity against S. aureus and to elucidate the molecular mechanisms underlying the antimicrobial synergy. P. longum extracts in ethyl acetate, n-butane, and methanol solvents are good candidates for future research.

Acknowledgment

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The authors extend their thanks to the anonymous reviewers for their insightful comments that helped improve the quality of this manuscript.

Conflict of Interest

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The authors have no financial conflicts of interest to declare.

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